Conditions: Bacterial Conjunctivitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
A randomized, double blind, phase II multicenter trial with the objective of assess the safety and efficacy of the PRO-157 ophthalmic solution in three different dosing regimens, versus Moxifloxacin, versus Gatifloxacin in patients with bacterial conjunctivitis.

Number of participants: 300 eyes, 60 per group.

Criteria for evaluation:

Measurements of effectiveness: Main efficacy criterion It will be determined as effective if there is a reduction in number or species of bacterial flora by comparing the basal culture against the final culture among the five different patient groups.

Reduction or absence of infection with the clinical evaluation through signs and symptoms.

Safety Measurements: it will be determined by visual acuity and adverse events Patients recruited will be treated for 7, for protocol purpose, the infected eye (s) will be taken into account at the time of baseline, however the study medication and procedures will be applied and performed in both eyes to protect the healthy eye.

The study is divided into the following evaluation periods:

Visit 1 baseline (day 1), visit 2 (day 3), final visit (day 8) and a telephone call (day 23) for the evaluation of adverse events.

Subjects will be allocated to any of the following regimen dosages:

* PRO-157 1 drop 2 times daily
* PRO-157 1 drop 3 times daily
* PRO-157 1 drop 4 times daily
* Moxifloxacin 1 drop 3 times daily
* Gatifloxacin 1 drop 3 times daily. All regimen dosage will have a duration of 7 days. An artificial tear preservative free (Lagricel Ofteno®) will also be applied 15 minutes before instillation of study drug, during study period.

Data Analysis: The data will be analyzed by Intention to Treat (ITT) and per Protocol (PP) in which each of the variables is described, the ITT population will be constituted by all subjects recruited who have received at least one dose of the study, the PP population will be the subset of ITT composed of all subjects without any major deviation from the protocol and the bivariate analysis will be performed in this group.

Continuous quantitative variables are expressed and presented by measures of central tendency and dispersion (mean, standard deviation and ranges). Qualitative nominal and ordinal variables are presented by means of frequencies and proportions. The level of significance was an alpha of 0.05 or less.

Detailed description:
Lagricel Ofteno® is a registered trademark, therefore the use of the same throughout the document can not be translated into the English language.

PRO-157, the acronym is part of an internal code used to record formulations or research projects and the numbers indicate consecutive of the molecule under study.

Arms:
arm 1: 60 eyes of 30 research subjects will be evaluated with the following therapeutic regimen:

1. instill one drop in each eye of PRO-157 (pazufloxacin), every 12 hours per day (BID), for 7 days
2. instill one drop in each eye of Lagricel Ofteno® (Sodium hyaluronate 0.4%)every 6 hours per day, for 7 days. (Can be applied 15 minutes after PRO 157) arm 2: 60 eyes of 30 research subjects will be evaluated with the following therapeutic regimen:

1. instill one drop in each eye of PRO-157 (pazufloxacin), every 8 hours per day (TID), for 7 days
2. 15 minutes after, instill one drop in each eye of Lagricel Ofteno® (Sodium hyaluronate 0.4%) every 6 hours per day, for 7 days. (Can be applied 15 minutes after PRO 157) arm 3: 60 eyes of 30 research subjects will be evaluated with the following therapeutic regimen:

1. instill one drop in each eye of PRO-157 (pazufloxacin), every 6 hours per day (QID), for 7 days
2. 15 minutes after, instill one drop in each eye of Lagricel Ofteno® (Sodium hyaluronate 0.4%) every 6 hours per day, for 7 days. (Can be applied 15 minutes after PRO 157) arm 4: 60 eyes of 30 research subjects will be evaluated with the following therapeutic regimen:

1. instill one drop in each eye of Moxifloxacin, every 8 hours per day, for 7 days.
2. 15 minutes after, instill one drop in each eye of Lagricel Ofteno® (Sodium hyaluronate 0.4%) every 6 hours per day for 7 days. (Can be applied 15 minutes after moxifloxacin) arm 5: 60 eyes of 30 research subjects will be evaluated with the following therapeutic regimen:

1. instill one drop in each eye of Gatifloxacin, every 8 hours per day, for 7 days.
2. 15 minutes after, instill one drop in each eye of Lagricel Ofteno® (Sodium hyaluronate 0.4%) every 6 hours per day for 7 days.one drop 4 times a day for 7 days in each eye.(Can be applied 15 minutes after gatifloxacin)

Interventions: intervention 1: PRO-157 intervention 2: Vigamox intervention 3: Zymar® intervention 4: Lagricel Ofteno®
Intervention descriptions: intervention 1: PRO-157 (Pazufloxacin 0.06%) Laboratories Sophia S.A. de C.V., ophthalmic solution intervention 2: Vigamox® (Moxifloxacin 0.5%), Alcon Laboratories, S.A. de C.V., ophthalmic solution intervention 3: Zymar® (Gatifloxacin 0.3%), Allergan, S.A. de C.V., ophthalmic solution intervention 4: Lagricel Ofteno® Sodium hyaluronate 0.4%, Laboratories Sophia S.A. de C.V., ophthalmic solution

Protocol document:
Prot_SAP_000.pdf: 
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Title of the document  
 Clinical Research Protocol 
 
Title of the study 
Phase II, multi-center, randomized, double-masked clinical 
study to evaluate the safety and efficacy of the PRO-157 
ophthalmic solution in three different posologies versus 
Moxifloxacin and versus Gatifloxacin in patients with 
bacterial conjunctivitis. 
Study drug  
 Pazufloxacin 
Indication  
 Antibiotic for the treatment of bacterial conjunctivitis 
Development phase  
 Phase II 
 
Protocol Code  
 SOPH157 - 0114 / II 
 
Sponsor  
 Sophia Laboratories, S.A. of C.V. 
Version 4  
 April 2016 
 
 
 
 
 


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1.- SUMMARY STUDY 
 
Sponsor's name: Laboratorios Sophia, S.A. of C.V. 
 
 
Finished Product Name: NA 
 
 
Active Ingredient Name: Pazufloxacin 
 
 
 
Title of the study: Phase II clinical study, multicenter, randomized, double masked to evaluate the 
safety and efficacy of the ophthalmic solution PRO-157 in three different posologies versus 
Moxifloxacin and versus Gatifloxacin in patients with bacterial conjunctivitis. 
Study centers: To be defined 
Study period: 7 days 
Phase of development of the 
study: Phase II 
Objectives: 
General purpose: 
To evaluate the safety and efficacy of the ophthalmic solution PRO-157 in three different 
posologies versus Moxifloxacin and versus Gatifloxacin in patients with bacterial conjunctivitis. 
Specific objectives: 
To determine the safety of the PRO-157 solution in three different posologies versus Moxifloxacin 
and versus Gatifloxacin in patients with bacterial conjunctivitis by the incidence of adverse events.  
To evaluate the efficacy of the ophthalmic solution PRO-157 in three different posologies versus 
Moxifloxacin versus Gatifloxacin in patients with bacterial conjunctivitis through the evaluation of 
ocular signs and symptoms such as: burning, lacrimation, foreign body sensation, pruritus, 
photophobia, hyperemia conjunctival, chemosis, secretion, membranes and / or 
pseudomembranes, scales and palpebral edema, epitheliopathy. 
Work hypothesis 
 
The ophthalmic solution PRO-157 is so safe and effective in any of its different posologies when 
demonstrating non-inferiority when compared against Moxifloxacin and Gatifloxacin in the 
treatment of bacterial conjunctivitis. 
Ho: The ophthalmic solution PRO-157 is not as safe and effective in any of its different dosages 
when demonstrating non-inferiority when compared against Moxifloxacin and Gatifloxacin in the 
treatment of conjunctivitis 
Ha: The ophthalmic solution PRO-157 is so safe and effective in some of its different posologies 
when demonstrating non-inferiority when compared against Moxifloxacin and Gatifloxacin in the 
treatment of conjunctivitis 
 


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Sponsor's name: Laboratorios Sophia, S.A. of C.V. 
 
 
Finished Product Name: NA 
 
 
Active Ingredient Name: Pazufloxacin 
 
 
 
Methodology 
Multicentric double randomized study masked. 
Number of participants: 300 eyes, 60 eyes per treatment group 
Diagnosis and main criteria for inclusion 
Patients with bacterial conjunctivitis (signs and / or symptoms and / or culture) 
Subjects aged 0 years to 99 years. 
Study medication: 
Pazufloxacin 
 
- 
Treatment duration: 
- 
- Recruitment period: 4 months 
- 
- Period of treatment: 7 days 
- 
- Period of follow-up: 15 days 
Criteria for evaluation: 
Efficacy measurements: 
 
Main efficacy criterion 
 
It will be determined as effective if there is a reduction in the number or species of bacterial flora 
comparing the basal culture against the final between the five different groups of patients and / or if 
there is a reduction or absence of the infection with the clinical evaluation through signs and 
symptoms such as: burning, tearing, foreign body sensation, pruritus, 
 photophobia, conjunctival hyperemia, chemosis, secretion, palpebral edema, membranes and / or 
pseudomembranes, palpebral scales and epitheliopathy 
Security measurements: 
 
Visual ability 
Adverse events 
 


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INDICE 
 
 
 
1. Summary of the study .. ....................................................... ................... .................... ..……2 
2. Glossary and definitions .. ......................................................... .. ...... .. ... ................. ... ... .6 
3. Administrative structure of the study .. ........................................ ............... ....................... 7 
3.1 Parties not sponsored. ............................................................ .. ... ... ... ....................... .... 7 
3.2 Sponsored parties .. ...................................................................... ... ............................ .... 8 
4. Background information .. ...................................................... ...................... ... ………………..8 
4.1 Justification .. ................................................................................. ................... .... ... ………9 
4.2 Non-clinical pharmacology .................................................................. ........................……11 
5. Clinical Studies ... .. ........................................................................ .................................... 17 
6. Hypothesis and Objectives ..................................................................... .. ..................... ... 17 
6.1 Work hypothesis ..................................................................... ..................... ...... …………..17 
6.2 Objectives. ............. .................................................................. ....................... . ...... ……..19 
7. Point or points limit ............................................................... .................... ...... ... …………..19 
8. Study plan .............................. .. ........................... .................... ......... ............ ………………..25 
9. Measures to minimize deviations .............................. ..................... ...... ………………………….29 
10. Products administered ............................................................... ..................... ... …………..30 
11. Description of the packaging ......................................................... ..................... ......... ….31 
12. Management of the study medication .................................... ..................... ............. ... ..31 
13. Closure of the center ........ ............. ........................................................................ .... ... .33 
13.1 Premature discontinuation of study ......... ...................... .................................... ... ...….31 
13.2 Center closure ......................................................... ..................... .................. ....…….…..31 
14. Source data .............................................................................. .................... ... ... …….…….33 
15. Selection and withdrawal of subject of study ............................................. ..................... 33 
15.1 Inclusion criteria ............................................................. ... .. ... ..................... ... …………..33 
15.2 Exclusion criteria .................................................................. ....................... ... ……………..34 
15.3 Criteria for patient withdrawal ....................................... .................... ............ .... ………..36 
16. Treatment of the study subjects ................................................ ........................ …………….37 
16.1 Managed treatments ...................................................... .. .... ... ..................... ……………..37 
16.2 Delivery of treatment ............................................................ .. .... ... ..................... ……….37 
16.3 Previous and concomitant treatments .............................. .................... ...... .. ... .. ... ……37 
16.4 Treatments authorized during the study .................................. .... ... ..................... ……….39 
16.5 Drug compliance ................................................... ..................... .... ... …………………………..39 
17. Methods and times of measurements ....................................... ..................... ...... .. ...…...39 
18. Security assessment. ... .. ................................................ .................... ....... ... …………………43 
18.1 Security measurements ....................................... .................... .................. .. ... .... ... ……43 
18.2 Times of measurements ......................................................... ...................... ...... ………….43 
19. Pregnancy test ... .. ......................................................... ....................... .………………………..45 
 
 
 
 
 
 
 


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20. Adverse events .................................................................. .................... ....... ... ……………..45 
20.1 Events to be registered .................................................................. .. ... .................... ... ..45 
20.2 Method for registration ............................................................... ................... ... .... ……..46 
20.3 EA Tracking ... ................................................... ................... ............... .. ... ... ……………….46 
20.4 Procedure for a serious EA .......................................... .. ... ................... ............ …………..47 
21. Assessment of Causation .................................................... ... ................... ... ... .... ………..48 
22. Responsibility of the sponsor ........................................... ... ................... ... ... ... ……………49 
23. Statistics ............................................................ .................. ............. ... .. ... ... ... …………..49 
24. Direct access to data / source documents ............ .. .................. ...................... ... ………….55 
25. Quality control and quality assurance ............. .... ............... .............. .... ... …………………..55 
25.1 Supervision of the study ................................................... .. ... .............. ................ ... ….55 
25.2 Computerized medical record ... ........................... .............. .......... ................ ... …………56 
25.3 Audit- Inspection-Certification .. ..................................... .................. ............... ... ……….56 
26. Ethics ... ............................................................................... .......... ... ............ .. ...... ………57 
26.1 Research Ethics Committee ...................................................... ................. ...... …………..57 
26.2 Conducting the study ..................................................................... ................ ... …….……57 
26.3 Information for the subject and form of informed consent .... ............ .................... ……57 
26.4 Modification to "informed consent" ... .. ......................... ............ ............... ... ..... ………58 
27. Data management and record keeping ....................................... ............... ... ... ….……….58 
27.1 Data of the study ...... ............................................................ .............. ....... ...... ….. ……58 
27.2 Form of case report ... ... ...................................................... ...................... ...... ………….58 
27.3 Data management ........................................................................ ... ...... ...................... 59 
27.4 File ..................................................................................... .... ...... ............... ……………….59 
28. Ownership of the results-Publication policy ......................... ....... ... .................. …………..59 
29. Administrative clauses .... ............................................................. ... ................ ... …………60 
29.1 People to inform .... ...................................................... ... ......... .. ...... ............... ………..60 
29.2 Substantial amendment to the protocol ... ................................................ .. .... ... ........ 60 
29.3 Final report of the study .... ......................................................... ...... ... ............... …….. 60 
29.4 Related to the sponsor ................................................ .. ....... ... ................ ………………….60 
30. Confidentiality of information ................................................ .. .... ... ................... …………60 
31. Organization of the center .... ............................................................. .... ... ................. ….61 
32. Documentation to be delivered .... .......................................................... .... ... ................ 61 
33. Appendices .................................................................................... ................ ... .. …………..62 
34. Bibliography ........................................................................... .............. ....... ... .. .... ……….77 
 
 
 
List of Paintings 
 
Table 1. Laboratories Sophia S.A. of C.V. .................................... .... ............................... .. ... 8 
Table 2. Schedule ............................................................ ... ................... ............ ………………..28 
Table 3. Description of the medication ................................. ... ................................. …………30 
Table 4. Main prohibited treatments ........................ ... ............................... ... …………………..38 
 
List of figures 
 
Figure 1. Curriculum ....................................................... ................................. ……………………20 
 
 


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List of appendices 
Appendix 1: Declaration of Helsinki of the World Medical Association .............................. ..62 
Appendix 2: Format for Pregnancy Tracking ......................................................................... 68 
Appendix 3: Report format of serious adverse events ........................................................ ..73 
Appendix 4: Inventory format and medication accounting ................................. ……………... 75 
Appendix 5: Humidity and temperature record of the drug for clinical studies ... …………….. 76 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. GLOSSARY AND DEFINITIONS 
 
 
 
EA 
 Adverse Event 
AV 
 Visual acuity  
CV 
 Visual Capacity 
FRC 
 Case Report Form 
BPC 
 Good Clinical Practices 
ICH 
 International Harmonization Conference 
CI 
 Informed Consent 
MY 
 Researcher's Manual 
CIE 
 Independent Ethics Committee 
CCI 
 Informed Consent Letter 
CRI 
 Institutional Review Committee 
ITT 
 Population Evaluable for Intent to Treat 
IOP 
 Intraocular Pressure 
PP 
 Estimatable Population by Proper Protocol 
EAS 
 Serious Adverse Event 
AMI 
 File Master of the Investigator 
AME  Master Studio File 
CP 
 Rear Camera 
ME 
 Study Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3 ADMINISTRATIVE STRUCTURE OF THE STUDY 
 
3.1 Non-sponsoring parties 
 
A central microbiological laboratory will be responsible for collecting and processing 
conjunctival sac fundus samples. 
 
3.2 Sponsoring parties 
 
Table 1. - Department of Clinical Research / Laboratories Sophia S.A. of C.V. 
Address: 
 
Sophia S.A. Laboratories de C.V., Paseo del Norte Av. No.5255, Guadalajara 
Technology Park, Carretera Guadalajara-Nogales Km13.5 C.P45010 Zapopan, Jalisco, 
Mexico Tel +52 (33) 3000 4200 
 
 
 
 
 
 
Function                                 Name / email                             Telephone number 
 
Clinical Operations 
Manager 
MBA Marco Antonio Cid López 
CCRP 
marco.cid@sophia.com.mx 
 
+33 3001 4200 Ext. 
1074 
scientific Comittee 
Dr. Aldo Arturo Oregon 
Miranda 
aldo.oregon@sophia.com.mx  
 
+33 3001 4200 Ext. 
1125 
Senior Monitor 
Q.F.B Jessica Mejía Gutiérrez 
jessica.mejia@sophia.com.mx 
 
+33 3001 4200 
Ext. 1192 
 
Junior Monitor 
Q.F.B Sandra Carolina Gómez 
Méndez 
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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4 INFORMATION ABOUT BACKGROUND 
4.1 INTRODUCTION 
 
Conjunctivitis (partial or total inflammation of the conjunctiva) caused by an external 
pathogen can be divided into bacterial and viral, however we must not forget that if we 
take into account its etiology we can name by fungal, allergic, autoimmune and by 
physical means (heat burns, friction, chemical). 
 
In the following document, we will concentrate on exposing the epidemiological and 
clinical panorama of conjunctivitis caused by pathogens (bacteria and viruses) and the 
suffering related to the mass. 
 
Currently about 6 million cases are registered per year in the general consultation (1% 
of the total annual consultations), this does not mean that all cases will be sent to the 
ophthalmologist, however as a reason for consultation 70% of the subjects come first 
with a family doctor and 35% refer to ophthalmologists because it is a case that does not 
remit with symptomatic or because the severity warrants it. 
 
The cost of treating conjunctivitis according to data collected in the American union 
represents more than 377 million dollars a year. 
 
Viral conjunctivitis: 
 
Viral conjunctivitis represents an average of 80% of reported cases, it is estimated that 
50% of these will be misdiagnosed as bacterial, this when compared to positive cultures. 
 
65-90% of cases are caused by adenoviruses found in any of its two pathogenic entities, 
either in the form of epidemic keratoconjunctivitis or pharyngo-conjunctival fever. 
Clinically both are characterized by local inflammatory reactions, hyaline secretion, 
chemosis, photophobia, hyperemia, corneal deposits and lymphadenopathy. 
 
The adenovirus is highly contagious and an estimated 10 to 50% chance of spread. 46% 
of the cultures in the hands of patients diagnosed with keratoconjunctivitis are positive, 
so their spread is verified mainly by contact and fomites. 
 
Its incubation period ranges from 5 to 12 days and its transmission period of 10-14 days. 
 
Its treatment consists of treating the symptoms with eye lubricants, NSAIDs, eye 
antihistamines, cold compresses, etc. Prophylaxis with antibiotics is not indicated since 
its benefit has not been proven, more if complications and delay in diagnosis of other 
entities are reported. 
 
 
 
Bacterial conjunctivitis: 


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Its incidence is estimated at 135 per 10,000 inhabitants. The main routes of infection are 
by contact, although the proliferation of normal flora can occur as sole etiology or 
concomitantly. 
 
The pathogenesis usually involves the disruption of the ocular surface defense 
mechanisms, due to trauma, tear film dysfunction or palpebral abnormalities, etc. 
 
Usually its installation occurs 1 to 2 days after contact, characterized by rapid 
appearance of clinical signs such as palpebral edema, hyperemia, mucopurulent 
secretion, membranes and / or pseudomembranes. 
 
The main infectious agents in adults are H. influenzae, staphylococci and streptococci. 
H. influenzae, S pneumoniae, and Moraxella catarrhalis are the most frequent agents in 
children. The course of the clinical picture is 7 to 10 days long. 
 
Due to its clinical presentation, it is convenient to divide them according to their 
installation time, in acute, acute or chronic hyperinflation, and can guide diagnostic tests 
and empirical treatment according to the time of presentation. 
 
 
Common pathogens according to the time of evolution 
 
 
Acute 
Híper Acute 
Chronic 
Staphilococcus Aureus. 
Neisseria Gonorreae. 
Moraxella 
catarrallis. 
Streptococcus pneumoniae. 
Neisseria meningitidis. 
Moraxella 
Lacunata. 
Haemophilus influenzae. 
 
Enterobacterias. 
 
Special conditions: 
 
In sexually active subjects who do not give up the clinical picture with empirical treatment 
(ceftriaxone 1gr b.i.d), we should investigate Chlamydia Trachomatis and add the 
relevant treatment. 
 
In the case of infants or minors (less than 2 years old), we should consider granting 
systemic treatment because 50% of them concur with infections in other systems. 
 
In oculo-vaginal infections we must investigate on strains compatible with trachoma (A-
C); since we must remember that it affects more than 40 million subjects in areas of poor 
hygiene and continues to be a leading cause in non-reversible blindness. 
 
 
 
4.1 JUSTIFICATION 
 
Conjunctivitis and bacterial keratitis are the pathologies of the ocular surface most 
commonly found in our environment. In general, they resolve spontaneously, however if 
they are not treated properly they can have irreversible consequences for visual health 


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(corneal ulcers, endophthalmitis, etc.), especially in patients who will be operated on 
ophthalmic surgery and / or senile, children, contact lens wearers, among others. 
 
These pathologies do not respect age, gender or social status. They are transmitted 
through contact with flush when talking to an infected person or through touch - hand - 
eye. Hence, it is quite common. The acute form of the infection is usually caused by 
Haemophilus species, S. pneumoniae, S. aureus or epidermidis, some of them normal 
habitual residents of the human conjunctiva. 
 
Its management, sometimes represents a diagnostic and therapeutic challenge for both 
the general practitioner and the ophthalmologist. The etiology of it is a very useful 
guidance to improve the patient's prognosis. Much of the morbidity produced by this 
pathology can be lessened with adequate therapy by reducing treatment time and 
comfort. Hence the importance of knowing the ocular pathogens commonly associated 
with our environment, isolating them in an accurate manner and correlating them with 
the specific characteristics of the patient. 
 
There are innumerable reports in the literature in this regard, however we have no 
knowledge of a specific one in our geographical area. The prevalence of Staphylococcus 
aureus 80 (23.7%), Staphylococcus albus 65 (19.2%), Pseudomonas aeruginosa 34 
(10.1%), Streptococcus pneumoniae 29 (8.6%), Haemophilus influenzae 26 (7.7%), 
Streptococcus pyogenes 20 has been recently published. (6.2%), Klebsiella pneumoniae 
18 (6.2%) Escherichia coli 15 (4.4%), Neisseria gonorrhoeae 13 (3.9%), Streptococcus 
viridans 11 (3.5%), Moraxella catarrhalis 10 (3.0%), among others, found that The most 
frequent isolations were made from the conjunctiva (66.7%) in contrast to the cornea 
(20.1%). These data correspond to the majority of what is published, however the 
socioeconomic and environmental conditions of the place where they were carried out 
are not the same to our region. 
 
In other regions, such as India (with characteristics probably similar to our environment) 
it is observed that S. Aureus frequently causes infections of the eyelids and conjunctiva, 
S. pneumoniae is responsible for those inherent to the lacrimal apparatus and S. 
coagulase negative corresponds to infections intraocular. 
In 10-year reviews in developed countries (eastern US) 1997- 2008, a tendency is 
observed in turn to the prevalence of Staphylococcus Aureus as the main ocular 
pathogen. 
 
The effectiveness of 4th generation quinolones in the treatment of bacterial conjunctivitis 
since 1 year of age with a posology that varies from 2 to 4 times a day has been 
demonstrated in recent evidence, which corresponds to the preclinical studies and phase 
I of the drug. viii 
 
We can also state the following points that support its use in infants and children under 
18 years. 
 
Due to the satisfactory results of the phase I study of the medication carried out in the 
adult population, in a phase II its implementation is justified in the child population since 
the evidence collected in said study allows inferring that its use is safe and effective to 
use it in the model of proposed disease, bacterial conjunctivitis. Ix 
 
 


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Also the incidence of adverse events of musculoskeletal toxicity in children with chronic 
use of quinolones of 4th generation is reported as not significant at 5-year follow-up, so 
it was concluded that its use is adequate in this population. viii, ix 
 
Currently, up to 26% resistance to the 4th generation quinolones (moxifloxacin, 
gatifloxacin and levofloxacin) is reported in strains of methicillin-resistant Staphilococcus 
epidemidis, so pazufloxacin represents a treatment option in such cases. ix, x 
 
 
Sophia S.A de C.V. has developed a new ocular topical formulation belonging to the 
group of the fourth-generation quinolones, called Pazufloxacin mesylate, which has 
shown through in vivo and in vitro studies to have greater antimicrobial activity against 
methicillin-resistant S. aureus, Haemophilus influenzae ampicillin resistant, as well as E. 
coli, Proteus mirabilis, Serratia marcecens and P. aeruginosa. It should be noted that 
this formulation is free of preservatives. 
 
Initially indicated for all those patients with bacterial conjunctivitis to susceptible 
organisms. 
 
 
Pazufloxacin has been clinically shown to be equally effective in the prophylaxis and 
control of ocular infections when compared to gatifloxacin, moxifloxacin, and levofloxacin 
in models of Staphylococcus aeurusix infections. This is the reason why we are 
interested in determining the consistency of these results with the Pro-157 formulation 
developed by Laboratorios Sophia SA de CV. 
 
 
 
4.2 NON-CLINICAL PHARMACOLOGY 
 
 
 
Distribution of pazufloxacin in vivo iv 
Sophia Laboratories were tested with three independent experiments in rabbits, which 
were separated into 6 groups, and slaughtered at times 15, 30, 60, 90, 120, 180 minutes 
to which they were applied exactly and only once 30 μL of the formulation under study 
(pazufloxacin 0.3%). The cornea and the aqueous humor were extracted and stored at -
20 ° C until the determination of pazufloxacin by HPLC. 
 
 
 
Distribution of pazufloxacin in cornea 
Table 1 shows the average concentration of pazufloxacin found per mg of cornea. 
 
 
 
 
 
 
Table 1. Average concentration of pazufloxacin found per mg of cornea  
 
 


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Minutes                           ng Pazufloxacin / mg cornea 
 
 
Calculation of pharmacokinetic parameters 
An entry is assumed as if it were intravenously and a first-order model of corneal removal. 
It also considers a volume of distribution in cornea of 0.08mL. It is considered that 30 mL 
of a solution of 3mg / 1000μL was added, which corresponds to a total amount of 90,000 
ng of pazufloxacin, Table 1. 
 
 
With regard to the concentrations in multiple dosing regimen, it can theoretically be said 
that the max and min concentrations of the drug follow different administration intervals 
(Table 3), based on pharmacokinetic parameters obtained from a single administration 
(Table 2, graphs 1 and 2).) 
 
 
Table 2. Pharmacokinetic parameters for pazufloxacin in cornea, calculated from 
the results of table 1. 
 
Parameter                                                   Value  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Graph 1. Representation of the behavior of the kinetics of pazufloxacin in the 
cornea following a first order reaction, simulating different dosage intervals. 
 


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Graph 2. Simulation of levels of pazufloxacin in cornea in vivo, dosing on the first 
day from 8 a.m. at 10 p.m. and resuming treatment at 6 a.m. of the next day. 
 
 
 
 
 
 
 
 
 


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Table 3. Maximum and minimum concentration in cornea in vivo (theoretical) 
reached in equilibrium, considering different dosage intervals. 
 
 
 
 
 
Distribution of pazufloxacin in aqueous humor 
For the calculation of pharmacokinetic parameters, a compartment model with 
first order absorption and elimination was followed. The volume of distribution for 
the aqueous humor of 0.25 mL, administration of 30 μL of a solution of 3mg / 
1000μL is considered, a total amount of 90,000 ng is obtained, Table 4 shows the 
average concentration found of pazufloxacin per mL of aqueous humor (Table 5). 
 
 
 
Table 4. Average found concentration of pazufloxacin per mL of aqueous humor. 
 
 
 
Table 5.- Pharmacokinetic parameters for pazufloxacin in aqueous humor, 
calculated from table 4. 
 
 
 
 
 
 
 
 
 
 


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The max and min concentration of the drug can theoretically be predicted by following 
different administration intervals (Table 6), based on pharmacokinetic parameters 
obtained from a single administration (table 5, graph 3 and 4). 
 
 
 
 
 
 
 
 
 
 
Table 6 Maximum and minimum concentration in aqueous humor reached at 
equilibrium considering different dosage intervals 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Graph 3. State of equilibrium in aqueous humor in different dosing times 
 
 
 
 
Graph 4.- Continuous administration during the day of 8 a.m. at 10 p.m. resuming 
treatment at 6 a.m. of the next day. 
 
 
 
 


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We also performed a preclinical study (PRO-0157-PZ), comparative randomized, 
unicentric, prospective, longitudinal and blinded in 30 rabbits (60 eyes) albino males New 
Zealand, whose objective was to compare and evaluate, safety as the toxicity of the 
topical ophthalmic solution of pazufloxacin vs Moxifloxacin hydrochloride and 
Gatifloxacin in the ocular surface in a clinical and histological manner. 
 
The allocation to the treatment group was randomly 1: 1, 10 rabbits were assigned for 
each treatment group, for purposes of the analysis both eyes were evaluated so the total 
number of eyes analyzed per treatment group was 20. The variables evaluated were: 
 
Conjunctival hyperemia, corneal surface, fluorescein staining, lysamine green stain and 
tonometry, presence of adverse events, red eye, lacrimation, findings in the revision of 
the periocular area and the anterior segment, findings in fundoscopy. In the 
histopathological study, histological changes were evaluated, as well as the toxicity in 
cornea, conjunctiva, ciliary body and retina. 
 
The results obtained showed that in the different visits very few cases were found with 
the presence of sign in the rabbits, also, when making the intergroup comparisons, only 
statistically significant differences were found (p = 0.036) for the variable chemosis in the 
evaluation corresponding to the day 30, where there were 4 (20%) reported cases in an 
area smaller than 25% of the total, 4 (20%) cases between 1 and 3, in the Moxifloxacin 
group a total of 11 (55%) cases were reported in an area smaller than 25% of the total, 
4 (20%) cases between 1 and 3, while in the Gatifloxacin group there were 4 (20%) and 
2 (10%) cases respectively. 
 
 
 
 


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It should be noted that in the rest of the variables evaluated the differences found were 
not statistically significant (p <0.05) 
 
 
 
5 CLINICAL STUDIES 
A phase I clinical study was conducted to evaluate the safety and tolerability of the 
PRO157 ophthalmic solution in healthy volunteers. The tolerability was determined by 
the presence of: burning, hyperemia, chemosis, foreign body sensation and lacrimation. 
Safety by assessing visual acuity and / or visual capacity, fluorescein staining, green 
lysine and intraocular pressure and the frequency of adverse events. A total of 5 visits 
were made. 
 
• Visit 0: Basal, day 0 (selection period). 
• Visit 1: Follow-up, day 2 (treatment period). 
• Visit 2: Follow-up, day 4 (treatment period). 
• Visit 3:. Follow-up, day 7 (treatment period). 
• Visit 4: Final day 11 (final visit). 
 
During which time the drop was applied 4 times a day in both eyes, the results that were 
obtained determined that the variables that reflect tolerability of the product, such as 
ocular burning, red eye, conjunctival hyperemia and lacrimation, remained 
predominantly in a low intensity (mild). There was no presence of chemosis or secretion. 
More than 88% of the eyes studied showed no sensation of a foreign body in the eye 
and more than 70% of the eyes did not present pruritus in the different evaluations. 
Variables that reflect the safety of the product, such as visual capacity and intraocular 
pressure, were always within normal parameters. No findings were reported during the 
revision of the anterior segment or the posterior segment, none of the eyes studied 
showed any degree of fluorescein or green lysine uptake in the corneal surface, there 
were no reports of adverse events. Vi 
 
 
6 HYPOTHESES AND OBJECTIVES OF THE STUDY 
 
        6.1 Working hypothesis 
 
The ophthalmic solution PRO-157 is so safe and effective in any of its different 
posologies when demonstrating non-inferiority when compared against Moxifloxacin and 
Gatifloxacin in the treatment of bacterial conjunctivitis. 
 
Ho: The ophthalmic solution PRO-157 is not as safe and effective in any of its different 
dosages when it shows no inferiority when compared to Moxifloxacin and Gatifloxacin in 
the treatment of conjunctivitis. 
 
Ha: The ophthalmic solution PRO-157 is so safe and effective in some of its different 
posologies when demonstrating non-inferiority when compared against Moxifloxacin and 
Gatifloxacin in the treatment of conjunctivitis. 
 
 
 
 
 


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6.2 Objectives 
 
 
General purpose: 
 
To evaluate the safety and efficacy of the ophthalmic solution PRO-157 in three different 
posologies versus Moxifloxacin and versus Gatifloxacin in patients with bacterial 
conjunctivitis. 
 
Specific objectives: 
 
To determine the safety of the PRO-157 solution in three different posologies versus 
Moxifloxacin and versus Gatifloxacin in patients with bacterial conjunctivitis by the 
incidence of adverse events and visual capacity. 
To evaluate the efficacy of the ophthalmic solution PRO-157 in three different posologies 
versus Moxifloxacin and versus Gatifloxacin in patients with bacterial conjunctivitis 
through conjunctival cul-de-sac culture and the clinical evaluation of some ocular signs 
and symptoms such as: burning, lacrimation, Foreign body sensation, pruritus, 
photophobia, conjunctival hyperemia, chemosis, secretion, palpebral edema, 
membranes and / or pseudomembranes, scales and epitheliopathy. 
 
 
7 STUDY DESIGN 
 
7.1 Point or limit points 
 
Criteria for the evaluation. 
 
 
Efficacy measurements: 
 
Main efficacy criterion 
 
Efficacy will be determined by taking cultures of the lower conjunctival cul-de-sac 
background quantifying (colony-forming units) and identifying genus and basal and final 
microbial species. 
It will be determined as effective if there is a reduction in the number or species of 
bacterial flora comparing the basal culture against the end between the five different 
groups of patients and / or if there is a reduction or absence of the following specific 
signs and symptoms: burning, tearing, Foreign body sensation, pruritus, photophobia, 
conjunctival hyperemia, chemosis, palpebral edema and secretion, membranes and / or 
pseudomembranes when comparing the study medication versus Moxifloxacin and 
versus Gatifloxacin from baseline to final visit. 
 
 
 
 
Efficiency parameters 
 
• The effectiveness of the drug will be evaluated by means of: 
 
 


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1. Clinical referral 
2. Microbiological remission 
Clinical remission will be evaluated by means of the signs and symptoms that the patient 
presents at the beginning and at the end of the study. 
Variable 
Operationalization 
Measurement 
scale 
Value 
Secretion 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Conjunctival 
hyperemia 
Dependent 
Qualitative ordinal 
Absent 
Mild 
Moderate 
Severe 
You must comply with the 
following: 
• Absent ≥ 95.0% 
• Mild ≤ 5.0% 
• Moderate ≤ 2.5% 
Severe ≤ 1.0% 
Chemosis 
Dependent 
Qualitative ordinal 
     Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Eyelid edema 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Corneal epithelial 
defects 
Dependent 
Qualitative ordinal 
Affected area, 
percentage 
Percentage of affected 
area less than 95% 
 
The microbiological remission will be evaluated by means of the culture taken from the 
conjunctival sac fundus. 
Variable 
Operationalization 
Measurement 
scale 
Value 
Culture 
Dependent 
Discrete quantitative 
UFC * / ml 
Eradication 
Reduction 
Proliferation 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
* Colony forming units 
 
 


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The drugs under study will be considered effective if the patient has any of the following: 
 
1. Clinical remission + Microbiological remission. 
2. Clinical referral. 
3. Microbiological remission. 
 
Security measurements: 
Adverse events and visual capacity. 
 
 
Evaluation parameters 
 
• The safety of the use of PRO-157 will be evaluated in the visits indicated in the schedule, 
through the following parameters: 
1. Visual capacity 
2. Eye surface 
3. Exploration of the previous segment 
4. Exploration of the posterior segment 
5. Burning 
6. Foreign body sensation 
7. Lachrymation 
8. Conjunctival hyperemia 
9. Itching 
10. Photophobia 
11. Chemosis 
12. Tear discharge 
13. Eyelid edema 
14. Membranes / pseudomembranes 
15. Scales 
16. Corneal epithelial defects 
17. Adverse events 
 
 
 
 
 
 
 
 
 
It will be considered that the drug under evaluation is safe for use in humans if there are no 
changes in the parameters indicated in more than 5% of the subjects, in both eyes, if the 


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patient goes to all the visits of the study and complies with adherence to treatment ≥ 80% 
during the time of evaluation of the study. 
 
 
Variable 
Operationalization 
Measurement 
scale 
Value 
Visual ability 
independent 
Discrete quantitative 
Points 
logMAR 
0-1 
0 = Snellen 
20/20  
 
Do not present change in 
1 line in the Snellen letter 
or in 1 logarithmic point 
(log MAR) 
 
Ocular surface 
Dependent 
Qualitative ordinal 
Absent 
Present 
 
Abnormalities in any area 
of the ocular Surface 
 
 
Exploration of the 
previous segment 
 
Dependent 
Qualitative ordinal 
 
Normal 
Abnormal 
 
Abnormalities in any of 
the structures included: 
cornea, iris, pupil, irido-
corneal and crystalline 
angle. 
 
 
Exploration of the 
posterior segment 
 
Dependent 
Qualitative ordinal 
 
Normal 
Abnormal 
 
Abnormalities in any of 
the structures included: 
vitreous, retina, macula 
and the optic nerve 
 
burning 
Dependent 
Qualitative ordinal 
Absent 
Present 
 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
strange body 
sensation 
Dependent 
Qualitative ordinal 
Absent 
Present 
 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
tearing 
Dependent 
Qualitative ordinal 
Absent 
Present 
 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
 
 
 
 
 
 
 
 
 
 


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Secretion 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
 
 
Conjunctival 
hyperemia 
 
Dependent 
Qualitative ordinal 
 
Absent 
Mild 
Moderate 
Severe 
 
You must comply with 
the following: 
Absent ≥ 95.0% 
Mild ≤ 5.0% 
Moderate ≤ 2.5% 
Severe ≤ 1.0% 
 
 
Photophobia 
Dependent 
Qualitative ordinal 
Absent 
Mild 
Moderate 
Severe 
You must comply with 
the following: 
Absent ≥ 95.0% 
Mild ≤ 5.0% 
Moderate ≤ 2.5% 
Severe ≤ 1.0% 
 
 
Chemosis 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Eyelid edema 
Dependent 
Qualitative ordinal 
Absent 
Present 
 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Memranas 
Pseudomembranes 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
Scales 
Dependent 
Qualitative ordinal 
Absent 
Present 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
 
 
 
 
 


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Epithelial defects 
corneal 
Dependent 
Qualitative ordinal 
Affected area, 
percentage 
Percentage of the 
affected area 95% 
Adverse events 
Dependent 
Qualitative ordinal 
serious 
Not Serious 
Must be recorded as 
absent in 95% of the 
subjects evaluated 
 
 
 
8 STUDY PLAN 
 
This is a phase II, randomized, double masked, multicentre, national study. 
 
This study will be carried out with 60 eyes with diagnosis of bacterial conjunctivitis, by 
treatment group, of patients of the ophthalmological consultation. 
 
Patients diagnosed with bacterial conjunctivitis (signs and / or symptoms and / or culture) 
recruited will be treated for 7 days with any of the three posologies of PRO157, 
Moxifloxacin, or Gatifloxacin. The randomization of any of the medications will be 
coordinated by a member of the research team previously designated who will not be 
masked and will be responsible for indicating to the patients how to apply the drops, 
emphasizing the patients of by no means mentioning the evaluating physician with the 
frequency who applies the study medication. 
 
No patient may use the aforementioned treatment more than the prescribed time. For 
purposes of the protocol, the infected eye (s) will be taken into account at baseline but 
the study medication and procedures will be applied and will always be done in both eyes 
to protect the healthy eye and the possibility of infection if Do not be infected from the 
beginning. 
 
The study is divided into the following periods: 
 
There will be a total of 3 visits which are divided into 1 baseline visit (day 1) 1 treatment 
visits (day 3), 1 final visit (day 8). A telephone call will finally be made to evaluate adverse 
events after 15 days of the last application of medication (day 23) 
 
At each visit from the baseline a clinical photograph of the eyes will be made, each of 
them must be identified by patient and visit number and delivered once the 30 patients 
are completed on a CD or USB. 
 
 
 
 
 
 


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1. Period of treatment of 7 days (from day 1 to 7) where any of the following posologies 
are applied according to randomization: 
 
  PRO157 1 drop 2 times a day in both eyes. 
  PRO157 1 drop 3 times a day in both eyes. 
  PRO157 1 drop 4 times a day in both eyes. 
  Moxifloxacin 1 drop 3 times a day in both eyes 
  Gatifloxacin1 drop 3 times a day in both eyes 
 
 
The study medications will be delivered by a coordinator (not blinded) or a person 
previously designated by the principal investigator, who will indicate how to apply the 
study medication according to the randomization and will place special emphasis on not 
mentioning the principal investigator or designee. perform the evaluations as the drop or 
any characteristic of the jars is applied. 
 
 
An artificial lagrima without conservative Lagricel Ofteno® will also be applied one drop 
4 times a day to all patients who enter the study during the 7 days of treatment with the 
study medication. 
 
 
 
The valuation days indicated in Figure 1 of the Study Plan must be carefully observed. 
A variation of  1 days can be accepted in relation to the inclusion visit (from day 1 to 8). 
In the case of the inclusion of subjects from 0 years to less 18 years minus 1 day, they 
will be included progressively as follow: 
 
 
• Age group of 12 to 18 years. 
• Age group from 2 to 12 years old. 
• Age group from 0 to 12 years old. 
 
 
This with the intention of integrating patients once the dosage parameters have been 
established as safe and recommended for the younger age groups. 
The indications of the inclusion periods will be made as the results are gathered in the 
groups of minors. 
 
 
 
Blinding 
 
The double-blind study is a procedure in which the patient and the attending physician 
do not know which of the intervention groups was assigned by the study patient. 
The blinding codes are protected by a person outside the study. 
 
 
 
 
 


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Figure 1 - Plan of the Study 
 
 
 
 
 
 
 
 
 
30 patients per study center 


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Table 2: Timeline 
 
A) Burning B) Lachrymation C) Foreign body sensation D) Pruritus E) Photophobia DF) 
Conjunctival hyperemia G) Chemosis H) Secretion I) Eyelid edema J) Membranes and / 
or pseudo-membranes K) Epitheliopathy L) Vitreous M) Retina N) macula O) optic nerve. 
 
 
 
 
 
Procedimiento 
  
 
Visita 
Basal 
 
  
Visita 
1 
 
Visita 
Final 
 
Seguimiento 
Telefónico EA 
Visita no 
programada / 
Descontinuaci
ón 
Día 1 
Día  3 
Día 8 
Día 23 
 
Criterios de Elegibilidad 
X 
 
 
 
 
Firma de consentimiento informado 
X 
 
 
 
 
Datos demográficos 
X 
 
 
 
 
Prueba de embarazo en orina (si aplica) 
X 
 
X 
 
 
Historia Clínica General y Oftalmológica 
X 
 
 
 
 
Padecimiento actual 
 
 
 
 
X 
Toma de muestra para cultivo 
X 
 
X 
 
 
Fotografía clínica de los ojos 
X 
X 
X 
 
 
Asignación de número al paciente 
X 
 
 
 
 
Entrega de medicamento 
X 
 
 
 
 
Inicio de aplicación de medicamento 
X 
 
 
 
 
Aplicación de medicamento 
X 
X 
X 
 
 
Devolución de medicamento por parte 
del paciente 
 
 
X 
 
 
Sintomatología Ocular (A,B,C,D) 
X 
X 
X 
 
X 
Agudeza y/o Capacidad Visual  
X 
X 
X 
 
X 
Biomicroscopia anterior (F,G,H,I,J,K) 
X 
X 
X 
 
X 
Tinciones de fluoresceína/verde de 
lisamina  
X 
X 
X 
 
 
Revisión del segmento posterior 
(L,M,N,O)  
X 
X 
X 
 
X 
Evaluación de eventos adversos  
X 
X 
X 
X 
X 
Evaluación de medicamentos 
concomitantes  
X 
X 
X 
 
X 


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9 MEASURES TO REDUCE DEVIATIONS TO MINIMUM 
 
On the other hand, adherence to treatment will be evaluated as follows: 
 
- With the study medication accounting returned. 
 
- Patients will have a "diary of the subject" where time of application of the drop and any 
incident or mishap at the time of the application of the drop, for example forgetfulness in 
the application of the drop, application of extra drops etc. will be noted. 
- The adherence to treatment must be greater than 80%. 
 
 
Example: 
 
 
A meeting of researchers will be organized for the physicians involved in the study before 
beginning with the inclusion of subjects. And your attendance will be mandatory. 
 
At the end of the study the patients will answer a questionnaire of satisfaction of the 
subject in the local language and the researcher will explain to the subject how to answer 
it. It is not authorized for the researcher to report / correct the qualification of the subject 
in the self-qualification questionnaires. 
 
 
 


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10 ADMINISTERED PRODUCTS 
 
Table 3. Description of study drugs 
 
Ophthalmic drops PRO157 
  
 
- Chemical name: 
 
Pazufloxacin mesylate [S - (-) - 10- (1-aminociclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-
dihydro-7H-pyrido (1, 2,3-de) (1, 4) -benzoxazine-6-carboxylic acid monomethanosulfate. 
 
- Molecular weight: 
  
414.41g / mol 
 
-Molecular formula: 
 
C16H15FN2O4 • CH3SO3H 
 
- Chemical structure: 
  
 
 
 
 
 
 
 


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11 DESCRIPTION OF THE PACKAGING 
Multi-dose bottle 
Primary packaging 
 
 
 
 
 
Secondary package 
The primary packaging will be contained in a secondary packaging in which the patient's initials 
and the researcher's name will have to be noted; It will also contain information on drug 
management as shown in the example. 
 
Example 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 MANAGEMENT OF THE STUDY MEDICINE 
 
The medications will be supplied from the manufacturing site (Sophia SA Laboratories 
of C.V.) previously weighed. 
The management of the study medication will be under the responsibility of the 
researcher and / or pharmacist of the health care establishment (when applicable), 
including: 
 
 
 
 
 
 
PRO157 
Solución oftálmica 
 
Contenido: 5 mL 
PRECAUCIÓN: MEDICAMENTO DE 
ESTUDIO. 
LIMITADO SÓLO PARA USO DE 
INVESTIGACIÓN 
Paciente No:   
Iniciales: _________ 
No. ME.:  
Lote:  
Cad:  
No. de medicamento:  
                                   Lote: 
Fecha de caducidad: 
PRO157 
Protocolo: SOPH157 - 0114/II  
No. de paciente: ______________ 
Iniciales del paciente: 
__________ 
Investigador:_____________ 
 
Vía Oftálmica. Administrar según lo 
indicado en el protocolo.  
DESPRENDER 
ETIQUETA 
PRO-157 
Protocolo: 
SOPH157 - 
0114/II  
 
                  
PRO-157 
Protocolo: 
SOPH157 - 
0114/II  


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- The reception and storage of the study medication (ME). The receipt of the study 
medication will be charged by signing and returning the medication delivery form. The 
study medication must be stored in a secure area with restricted access. Some special 
storage conditions are requested 
• The PRO-157 ophthalmic solution should be stored at room temperature to no more 
than 30 ° C, 
• The bottle must be kept tightly closed. 
 
The investigating doctor or the person previously designated in the delegation of 
responsibility format is obliged to keep a documented record of humidity and minimum 
and maximum daily temperatures on one occasion a day, for the realization of these 
measurements, Sophia Laboratories will provide a thermo hygrometer which will be 
returned at the end of the clinical study. 
 
- The discharge of the thermo hygrometer data will be done by the clinical monitor during 
the monitoring visits. 
 
- The expiration date will appear on each box and label of the investigational medication. 
- The delivery of the study medication will be in accordance with the study plan and 
following the delivery methods described in the section. The researcher and / or 
pharmacist of the health care establishment should use the treatment delivered only for 
the patients participating in the study. 
- The study medication count. 
 
The investigating physician and / or a previously designated responsible person of your 
study team must fill out in real time all the documents that the sponsor provides for the 
management of the study medication (acknowledgment of receipt in the shipping 
formats, tracking form of study medication). 
  
 The study monitor will periodically check the management and counting of the 
medication under study. 
 
At the end of the study, the researcher and the study monitor will perform the final count 
of the medication, and it will be recorded in the corresponding format. 
The study monitor will collect and send to Laboratorios Sophia S.A. of C.V. the remaining 
study drugs, for storage and subsequent destruction, after quantification thereof. 
 
All defects or deterioration of medications or their packaging must be reported to the 
study monitor. The investigator will notify the monitor of all complaints received from a 
patient. 
 
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 receipt of the letter, the investigator and / or pharmacist will identify the 
patients who have the treatment in their possession at the time the incident is known, 
using the tracking form of the study medication, and will contact them immediately. . The 
monitor will organize the return of the study medication to proceed with its destruction. 
 
 
 
 


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13 CENTER CLOSURE 
13.1 Premature discontinuation of the study 
The sponsor may terminate the study before the scheduled deadline. A written 
confirmation will be sent to the researcher informing him that the clinical study is 
terminated. 
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 Ethics Committees and the Competent Authorities will be informed in accordance 
with local regulations. 
13.2 Closure of the center 
Any center that has finished including the last patient previously stipulated; and that this 
has complied with the days of study treatment and the safety visit; It may be closed if 
there is a common agreement between the sponsor and the study center. 
14 DATA SOURCE 
The following data (s) will be considered as source: 
- The patient's medical file, notes of interconsultation, results of clinical laboratories, 
results of cabinet examinations. 
- Patient's diary, 
- Self-qualification questionnaires (subject satisfaction questionnaire) 
The patient will directly record the data in the patient questionnaire and in the paper self-
assessment questionnaires (subject satisfaction questionnaire), which will be considered 
source data. 
15 SELECTION AND WITHDRAWAL OF SUBJECTS OF STUDY. 
Eligibility Criteria 
 15.1 Inclusion Criteria 
All selected subjects: 
- They will have an age between 0 to 99 years * see note. 
- They will be obtained in the external consultation. 
- With diagnosis of bacterial conjunctivitis (signs and / or symptoms and / or culture) 
- Signed and dated Informed Consent (Informed Consent and parental consent in case 
of being a minor) 
* NOTE: In the case of inclusion of subjects from 0 years to less 18 years minus 1 day, they will 
be included progressively as follows: 
• Age group of 12 to 18 years. 
• Age group from 2 to 12 years old. 
• Age group from 0 to 2 years. 


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This with the intention of integrating patients once the dosage parameters have been 
established as safe and recommended for the younger age groups. 
The indications of the inclusion periods will be made as the results are gathered in the 
groups of minors. 
The Informed Assent will only apply to minors who demonstrate understanding of 
the study, at the discretion of the researcher. 
 
- Physical examination of patients 
In the examination carried out during the baseline visit, a general and ophthalmological 
clinical history will be performed, initially including and starting treatment with all those 
patients clinically suspected of bacterial conjunctivitis. If the culture is negative but 
clinically there is improvement, you can continue with the treatment until the last day of 
the stipulated study. At the baseline visit a urine pregnancy test will be performed (if 
applicable). 
15.2 Exclusion criteria 
         General 
1. Lack of written informed consent. 
2. Women with the possibility of having children, without using contraception (oral 
contraceptive pill, intrauterine contraceptive device, contraceptive implant, patch or condom). 
3. Pregnant women or breastfeeding. 
4. Subjects that can not be assessed partially or totally according to the protocol. 
5. Subjects with topical, systemic or intravenous medication with any type of antibiotic on the 
day of the baseline visit. 
6. Subjects with topical, systemic or intravenous medication with any type of medication that 
interferes decisively with the results of the study. 
7. Subjects with a history of hypersensitivity to any of the components of the formula of the 
research product or its analogues. 
8. Positive substance abuse (smoking, alcoholism, marijuana). * 
9. Subjects who have participated in any clinical research study in the last 40 days, prior to 
inclusion in the study. 
10. Subjects legally or mentally incapacitated to give their consent to participate in this study. 
11. Any clinically important abnormalities detected during the clinical examination, tests that 
could interfere with the conduct of the study or with the evaluations of efficacy and safety. 
 
* Repeated consumption of one or several psychoactive substances, to the point that the consumer (known as an addict) 
becomes intoxicated periodically or continuously, shows a compulsive desire to consume the preferred substance (or 
substances), has an enormous difficulty interrupting voluntarily or modify the consumption of the substance and is 
determined to obtain it in any way. -Definition of WHO * 
 
 
 


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Related to ophthalmological criteria 
 
1. Eye surgery in the past 6 weeks. 
2. Active ulcerative keratitis. 
3. Recurrent corneal erosion syndrome. 
4. Suspected viral or allergic conjunctivitis. 
 
Related to a therapy or previous and / or concomitant treatments 
 
Current therapy or expected therapy with: 
 Systemic NSAIDs, corticosteroids, antihistamines or immunosuppressants. 
Typically, patients can not be treated at the baseline visit with any other type of antibiotic 
topical ophthalmic, as well as steroids, NSAIDs, mast cell stabilizers, antihistamines, 
decongestants. If the patients prior to this day were under treatment with another 
antibiotic or drugs of those mentioned may be included. 
To know the other prohibited treatments and their rest period, please refer to Table 4 
"Main prohibited treatments" 
 
Elimination Criteria 
 
• Any complication or lack of control that the doctor considers should be treated 
differently. 
• Elimination Criteria 
• Clinicians: 
 
a. Any complication or lack of control that the doctor considers should be treated 
differently. The following points should be considered: 
 
i. The no improvement of the initial clinical signs and symptoms. 
ii. Diagnosis added or different to that of acute bacterial conjunctivitis. 
iii. Use other medications outside the study. 
 
b. * It is reiterated that they are minimum parameters to be considered, any other case 
in which the investigator considers necessary the elimination of the patient and 
suspension of the treatment must be informed and evaluated by the sponsor. 
 
 
 


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• For the sponsor: 
 
a. By its will, it will not have penalties, nor will it lose benefits to those that it already has 
right. 
b. For the total term of the scheduled visits in the clinical study. 
c. For a serious adverse event related to the medication that endangers your health. 
d. Why the medication does not work at the doctor's discretion. 
and. Why, by sponsor's decision, the study ends earlier. 
 
In case of withdrawal for any of these reasons or any other at the discretion of your 
doctor, you will be prescribed again the medication of which you were already a user or 
any other that is of benefit for your best treatment. 
 
15.3 Criteria for the premature withdrawal of the subject 
Criteria for premature withdrawal 
The following criteria will cause a mandatory withdrawal from the study: 
The reasons for a patient leaving the study prematurely may be the following: 
- Subject's decision. The patient 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 patient as soon as possible for a final evaluation in order to: 
• Document the patient's decision in clinical notes, 
• Obtain the reason (s) for the exit and write them down in the FRC exit format, 
• Evaluate the patient's clinical status, 
• If necessary, take the appropriate therapeutic measures: management of an adverse 
event. 
 
In case of failure of all these attempts to contact the patient, the investigator may declare 
"loss of follow-up" of the patient. The investigator will document all the attempts in the 
corresponding medical file. 
 
- Decision of the investigator. Especially if an adverse event occurs and the researcher 
considers that this may threaten the patient's health, or if an important disease occurs 
that requires the prescription of a medication incompatible with the objective of the study. 
 
- Need for another treatment according to the criteria of the Medical Investigator who will 
have to document it well in his notes. 
 
- Pregnancy (see procedure in Appendix 2) 
 
- Any deviation to the protocol that affects the patient's safety. 
 
- In all cases, the available data will be saved for the safety analysis (population 
evaluable by intention to treat). 
 
 
 
 


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Process 
 
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 patient 
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 FRC. If more than one reason is given, the investigator must indicate 
the main reason. 
In case of premature withdrawal from the study due to an adverse event (an event that 
is serious or not serious), the investigator should make every effort to gather information 
related to the outcome of the event. If necessary, the information will be collected later. 
This information will be recorded in the FRC part related to non-serious adverse events 
and serious adverse events in a format that will be given separately in case the 
investigator can not collect the information in a visit, then it will be obtained from the 
doctor who ensures the patient follow-up 
If the study is discontinued / the treatment is discontinued as a result of an event that 
requires immediate notification, the procedure described in the suspension or 
discontinuation section of the study will be implemented. 
 
16 TREATMENT OF STUDY SUBJECTS 
 
16.1 Managed treatments 
Lagricel Ofteno® Apply one drop 4 times a day for 7 days + any of the following according 
to the randomization in both eyes. 
 
Apply one drop of PRO157, 2 TIMES a day, from day 1 to day 7 
Apply one drop of PRO157, 3 TIMES a day, from day 1 to day 7 
Apply one drop of PRO157, 4 TIMES a day, from day 1 to day 7 
Apply a drop of Moxifloxacin, 3 TIMES a day, from day 1 to day 7 
Apply a drop of Gatifloxacin, 3 TIMES a day, from day 1 to day 7 
 
16.2 Delivery of the treatment 
The study drugs will be delivered by a coordinator (not blinded) or person previously 
designated by the principal investigator, who will indicate how to apply the study 
medication according to the randomization and will make special emphasis to each 
subject of not mentioning the principal investigator or person previously designated to 
perform the treatment evaluations as the drop or characteristic of the delivered bottles is 
applied. 
This is to keep the blind person in the subject's evaluator and avoid bias. 
 
16.3 Previous and concomitant treatments 
Prohibited treatments 
Table 4 shows the list of prohibited treatments during the study. 
If a prohibited treatment is absolutely necessary during the study, the subject should be 
removed from the study. 
 
 
 
 


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Table 4. Main prohibited treatments (during the study) 
 
 
Medicamento 
 
Vía de administración 
Grupo 
Prototipo 
 
Betalactámicos 
Penicilinas, Cefalosporinas, 
Monobactams, 
Carbapenems. 
Tópica 
Aminoglucósidos 
Gentamicina 
 
Tópica 
Azúcares complejos 
Clindamicina 
 
Sístemicas 
Polipeptídicos 
Polimixina 
 
Tópica 
Rifamicinas 
Rifampicina 
 
Sístemica 
Tetraciclinas 
Clortetraciclina 
 
Tópica 
Amfenicoles 
Cloramfenicol 
 
Tópica 
Macrólidos 
Eritromicina 
 
Sístemico 
Misceláneos 
Espectinomicina, 
Virginiamicina, Vancomicina, 
Teicoplanina, Capreomicina, 
Cicloserina, Fosfomicina, 
Novobiocina, Linezolida 
 
Tópica, Sístemico 
Quimioterapicos 
antibacterianos 
Sulfonamidas Sulfonamidas 
+ Trimetoprim 
Nitrofuranos Derivados de 
Naftiridinay Quinolonas 
Tópica, Sístemico 
Antiinflamatorios no 
esteroideos 
Ketorolaco. Diclofenaco, 
nepafenaco, meloxicam,  
Tópica 
Esteroides 
Prednisolona, 
dexametasona, 
triamcinolona, 
fluorometolona, loteprednol. 
Tópica, Sístemico 
Lagrimas artificiales con 
conservador 
 
Tópica 
Antihistamínicos 
Epinastina 
Tópica 
Descongestionantes 
Nafazolina , Oximetazolina, 
etc 
Tópica 
Estabilizadores de 
mastocitos 
Cromoglicato de Sodio, etc 
Tópica 
Quinolonas 3era o 4ta 
generación 
Moxifloxaciono. 
Gatifloxacino 
Tópica 
Quinolonas 2da, 3era o 
4ta 
Ciprofloxacino, 
Levofloxacino, Ofloxacino.  
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16.4 Authorized treatments during ophthalmologic exploration and / or course of 
study 
Tretacaine hydrochloride (during ophthalmologic exploration) 
Tropicamide / Phenylephrine Hydrochloride (during ophthalmologic exploration) 
Lagricel Ofteno® (during the whole study time) 
16.5 Compliance with treatment 
- With the accounting of the study medication returned. 
 
- Patients 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, for example, 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. 
 
17. Methods and times of measurements. 
 
Scales to fill out by the researcher: 
 
A meeting of researchers will be organized for all those involved in carrying out the study 
before starting it, and their participation will be mandatory. The objective of these 
sessions is to train them on the assessment of the efficacy and safety criteria and to 
ensure reliability among the qualifiers. In addition, detailed qualification rules will be 
provided to the qualifiers 
The scales should always be evaluated by the same evaluating physician, either the 
principal investigator or an ophthalmologist previously designated in the Delegation of 
Responsibility format throughout the study, at the beginning of each visit. A guide will be 
made available for the interview to be carried out in each of the visits. 
 
Self-qualification questionnaires to be completed by the patient: 
Initials of the subject 
 
 
 
Mark with an X in any of the following options with which you have identified more in the 
course of the clinical study. 
 
 
 
DEGREE OF SATISFACTION OF THE SUBJECT 
ANSWER 
Very bad: Intense and unbearable nuisances. 
 
Mal: Moderate intensity, intermittent, not tolerable. 
 
Regular: Discomfort of moderate intensity, intermittent and tolerable. 
 
Good: Mild and occasional nuisances. 
 
Very good: No discomfort (absent). 
 


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The researcher will apply to the subject a questionnaire that he / she will have to answer 
at the end of the study where the satisfaction is evaluated upon finishing his / her 
participation in the study. 
 
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 patient 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 patient sees 
it. The smallest size that the patient recognizes will be taken as a threshold value and 
expressed in minutes of arc. Visual ability is the best corrected visual acuity. 
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 in log MAR the unit (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 "Golden Proof". 
 
Standardization of the visual examination: 
 
- At a distance of 3 m in a room with dim lighting, the research subject will be evaluated 
as follows: 
- This exam will be held at the research center 
- The patient will be asked to always sit in the same place and with the LogMar scale the 
visual acuity (AV) will be assessed if he / she does not have this type of booklet he / she 
must carry out the conversion. 
- The research subject will keep both eyes open. 
- The research subject should gently cover one eye with an occluder while reading aloud 
the smallest line of letters that can be seen. This test is done on each eye, one at a time, 
starting with the right eye (RE). 
- The doctor must point out, the line that is requested to read the research subject. 
- Finally, through the pinhole, the same procedure will be carried out. 
 
Normal values: visual acuity or visual capacity will be expressed in decimals, where 0.0 
will be the maximum normal score. In the case of people who do not know how to read, 
the test will be done with special cards of figures or numbers and the VA will be defined 
with the same LogMar scale, for patients of very early ages such as RN, infants or 
uncooperative preschoolers. AV as it perceives and follows light or does not perceive or 
follow light. 
In offices where LogMar is not available, you can measure the VA with the card you 
normally use and convert it to the LogMar scale for which the following table of 
equivalences helps. 
 
Equivalence between the different AV scales 


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Biomicroscopy Previous 
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. 
If any of the structures has any special description that you write down in comments of 
that same section in the FRC. 
 
Conjunctival hyperemia 
Which is defined as the simplest reaction of the conjunctiva to a stimulus, we see 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. Vii 
 
 
1.- Very Mild               2. Mild                        3.- Moderate             4.- Severe 
 
Foreign body sensation 
Burning 
Lachrymation 
Eyelid scales 
Eyelid edema 
Membranes and / or pseudomembranes 
Epitheliopathy 
These symptoms will be described as present or absent, 
Secretion will also have to be described 
 


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Fluorescein and green lysamin stain 
 
Fluorescein staining will be performed, standardization of this scan is done as follows: 
1. With the patient in front of the lamp prior instillation of topical anesthesia Ponti Ofteno 
that will be provided by Laboratorios Sophia, S.A. of C.V. 
2.- The lower eyelid of the patient will be gently grabbed, first on the right side and then 
on the left side, asking the patient to turn upwards so that with this maneuver a greater 
area of the lower bulbar conjunctiva is exposed, then the filter paper will be placed 
moistened with a drop of anesthetic and the surface of the eye will be touched with it for 
a second in the aforementioned area, subsequently the patient will be asked to blink 
several times and proceed to examine it without specifying corneal region, the same 
procedure will be performed for the analysis of the conjunctiva with lysamine green: 
 
Absent (without staining) 
Medium (less than 10% of the surface with staining) 
Moderate (from 10 to 50% with surface staining) 
Severe (more than 50% of the surface) 
 
Membranes and pseudomembranes 
They are formed by exudates adhering to the inflamed conjunctival epithelium, the 
difference between one and another is that the latter are removable. 
Your presence or absence will be reported. 
 
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. 
If any of the structures has any special description that you write down in comments of 
that same section in the FRC. 
 
 
Sampling for central laboratory: 
 
(This is a general procedure, it does not mean that it should be done as such, that 
procedure will be punctually described by the central laboratory where the crops will be 
sent). 
 
1.- After cleaning hands and putting on latex gloves. 
2.- Take the swab contained in the package of the means of transport with the index 
fingers and thumb of the right hand while with the index finger of the left hand the lower 
eyelid is gently pulled exposing the bottom of the bag and thus be able to take the sample 
of it 
3.- By touching the palpebral conjunctiva the applicator is rotated to take as much sample 
as possible. 
4.- Place the swab in the transport medium. 
 
The central laboratory in charge of the processing of the samples will be asked for Gram 
stain and special attention to the growth in the culture of the following bacteria: 
 
 


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Staphylococcus 
aureus, 
Staphylococcus 
albus, 
Pseudomonas 
aeruginosa, 
Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus pyogenes, 
Klebsiella pneumoniae Escherichia coli, Neisseria gonorrhoeae, Streptococcus viridans, 
Moraxella catarrhalis. 
 
The technique for collecting the sample will be done using a swab. These techniques are 
not limiting, and it is up to the doctor to select one of them according to the case. 
 
18. VALUATION OF SECURITY 
 
18.1 Safety measurements 
 
Figure (8.2.2) 1 - Research Program indicates safety measurements that are made in 
each visit or treatment period. 
       
Security criteria 
- Adverse events and visual ability 
 
18.2 Times of Measurements 
 
Clinical examination 
Basal visit (Day 1) 
 
The principal investigator or the head of the research team of the site duly specified 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 and all the inclusion criteria and none of 
exclusion are met, a unique identification number of the subject will be assigned, this will 
be used throughout the study for its identification. 
 
 
Female subjects who are of reproductive age will be tested for pregnancy in urine. 
 
The following evaluations will be made: 
Signature of informed consent 
Review of inclusion criteria and exclusion criteria, 
Demographics, 
Urine pregnancy test (if applicable), 
General and ophthalmological clinical history, 
Clinical Photography, 
Sampling of conjunctival sac fundus for culture, 
Assigning number to the subject, 
Delivery of medication, 
Ocular symptoms: burning, tearing, foreign body sensation, pruritus, photophobia 
Visual acuity and / or visual ability, 
Anterior biomicroscopy: Conjunctival hyperemia, chemosis, secretion, palpebral 
edema, membranes and / or pseudomembranes, scales, epitheliopathy, 
Fluorescein staining, 


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Green stain of lysine, 
Posterior segment revision: Retina, Macula, Vitreous and Optic nerve. 
Evaluation of adverse events. 
 
 
This day the patient will be included, if clinically it suggests a bacterial conjunctivitis, it 
will be randomized and at that same moment a clinical photograph of his eyes will be 
made and a sample will be taken for culture of both eyes, immediately he will go with 
the person previously designated to randomize him , this person will not be masked 
and will give specific instructions to the patient on how to apply the study medication 
and will remember the importance of the patient not mentioning the study's evaluating 
physician how many times the treatment is applied, then he will start with the study 
medication regardless of the crop results. 
 
Treatment visits: 
Visit 1 (Day 3) 
Between the days of study there may be a window of ± 1 day. If for any reason an 
assessment is made on any day not planned in the study, this information should be 
recorded in the unscheduled visit format found within the FRC. 
 
At each follow-up visit, an ophthalmological examination will be performed in order to 
evaluate the following parameters. 
1. Acuity and / or Visual Ability 
2. Clinical Photography, 
3. Evaluation of specific symptoms and signs: burning, tearing, foreign body sensation, 
pruritus, photophobia, 
4. Anterior biomicroscopy: conjunctival hyperemia, chemosis, secretion, palpebral 
edema, membranes and / or pseudomembranes, scales, epitheliopathy. 
5. Posterior biomicroscopy (retina, vitreous, macula and optic nerve). 
6. Fluorescein staining 
7. Green lysine stain 
8. Evaluation of adverse events. 
9. Evaluation of concomitant medications. 
 
Final Visit (Day 8) 
In this the following parameters will be evaluated: 
1. Urine pregnancy test (if applicable) 
2. Return of medication by the subject 
3. Acuity and / or Visual capacity 
4. Clinical photography, 
5. Ocular symptoms: burning, tearing, foreign body sensation, pruritus, photophobia. 
6. Conjunctival sac fundus sampling for culture 
7. Anterior biomicroscopy: conjunctival hyperemia, chemosis, secretion, palpebral 
edema, membranes and / or pseudomembranes, scales, epitheliopathy. 
8. Posterior biomicroscopy (retina, vitreous, macula and optic nerve). 
9. Fluorescein staining 
10. Green lysine stain. 
11. Evaluation of adverse events 
12. Evaluation of concomitant medications 
 
Follow-up of Adverse Events (EA) (Day 23) 
 


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1. A telephone call will be made by the investigating doctor or responsible previously 
designated for the evaluation of adverse events. 
 
19. PROOF OF PREGNANCY 
 
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. This will be in private and then 
deliver the bottle with the urine sample to the investigating doctor or person in charge 
beforehand, who will introduce a test strip into the sample and wait for the result. 
 
20. ADVERSE EVENTS 
 
All adverse events should be subject to follow-up until their completion and documented 
in a complete and accurate manner in order to make possible the assessment of the 
safety of the study drug. 
 
20.1 Events to be registered 
 
An adverse event is defined as any unfavorable medical occurrence in a subject that is 
participating in a clinical trial, whether or not there is a causal relationship with the study 
drug and / or experimental procedures, that is present or detected as of the date that the 
patient signs the form of information and consent, regardless of the period of the study. 
 
 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 during the study of a symptom or disease already present when the 
patient entered the study (increase in frequency and / or intensity), and which: 
-It is detected during a study visit or in an additional examination, 
- Be present from the previous visit of the study and notify the patient. 
 
 
A serious adverse event, that is, an event that, regardless of the dose of the study drug 
administered: 
 
 
• How the patient's death results 
• Be a threat to life, 
Note: the term "threat to life" refers to an event in which the patient 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. 
 
• How persistent or important disability / disability results. Note: an event that seriously 
disrupts the patient's ability 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 patient, 
physical activity and / or quality of life. 
• Be 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. 
 


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Note: any event that may not be an immediate threat to life or result in death or 
hospitalization but may endanger the patient or may require intervention to avoid one of 
these outcomes (eg, edema or allergic bronchospasm requiring treatment) intensive at 
home, blood dyscrasia, seizures that do not cause hospitalization, or development of 
drug dependence or drug abuse). 
 
 
 
Consumption of the study drug by a person other than the patient: 
 
• 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 inform immediately by telephone or fax, 
or in non-working hours, to the 24-hour telephone line (see Table (12.3.1.3) 2). These 
cases should be reported on separate paper pages "Adverse Event" that will be provided 
to the centers and should be sent immediately by fax to the responsible person. 
• A pregnancy that occurs during the study. 
 
 
20.2 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 patient entered the study, it will only be 
documented as an adverse event when there is a worsening (increased 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 form "Adverse event". 
 
 
 
20.3 Follow-up of adverse events 
 
The researcher must ensure that the patient's follow-up is appropriate to the nature of 
the event, and that it continues 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 solved in the patient's final visit, the study can not be 
closed until it has reached a resolution, which must be followed by the principal 
investigator or the previously assigned responsible person, who must look for it. detail of 


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the adverse event and its follow-up only if the researcher indicates that this adverse 
event is directly related to the study medication. If it is not directly related, then it must 
be registered and the center can be closed. 
 
20.4 Procedure for a serious adverse event 
 
In the event of a serious adverse event and that is presented: 
- During the study. 
- During the 15 days following the final visit of the patient's study, regardless of the 
supposed function of the investigation (drug under study or experimental procedures 
required 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 related to the investigation. 
 
The researcher must: 
 
Record in the participant's medical record the date on which the event was made known 
(in a follow-up visit or through telephone contact with the participant or with a third party, 
...), immediately after being informed about this event , filling out a "Serious adverse 
event" form, without waiting for the clinical results or the results of additional research, 
will be informed by the sponsor (Clinical Research Department and Pharmacovigilance 
Department) by e-mail, (see Table (12.3.1.3) 1 ) .Provide people who are designated 
later, as they are available, anonymous copies of documents that offer useful additional 
information, such as hospital admission reports, other consultation reports, laboratory 
test reports, reports. of other tests that help the diagnosis (when possible, pre-treatment 
assessments should be attached to the stop them against the results obtained with the 
treatment), or the report of the autopsy, if done. 
- Comply with their regulatory obligations before the Competent Authorities and / or 
before the Ethics Committee, in compliance with local regulatory requirements. 
 
 
Table 5 - Contact structures in case of a serious or not serious Adverse Event. 
 
 
 
First contact 
 
Clinical Study Monitor 
QFB. Sandra Carolina Gómez Méndez 
Cel. 331 86 21 071 
+33 3001 42 00 
Ext. 1191 
 
LN. Ana Isabel Alcaraz Ledón 
Cel. 331 862 10 72 
+33 3001 4200 
Ext. 1193 
 
 
 
 
 


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QFB. Jessica L. Mejia Gutierrez 
Cel. 331 86 21 070 
+33 3001 4200 
Ext. 1192 
 
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 form "Serious adverse event" 
 
Report the initially not serious event on a paper page "Adverse event - Additional 
information" (see appendix 9), 
 
- Report the deterioration caused by the seriousness on a paper page "Adverse event - 
Additional information" (see appendix 10), and 
- Send them by email immediately to the responsible person indicated above. 
 
If a female patient in the study becomes pregnant, the investigator should: 
 
- Suspend the study treatment for the patient. 
- Fill out an "adverse event" form of the FRC. 
- Fill out a paper form of pregnancy follow-up report (first page, appendix 11), 
- Contribute to the follow-up of this pregnancy and provide the sponsor with the 
information related to this follow-up (mainly using the second page of the pregnancy 
follow-up report). 
 
 
21. EVALUATION OF CAUSALITY 
It is important that the investigator of your opinion in relation to 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 development program (for example: 
 
 
 
 


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Changes in dose, population of the study or in the information provided to patients that 
may lead to the preparation of new forms of information and consent). 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, mean a threat to life. 
 
The causality must be assessed at the time of writing in the patient's file; Subsequently, 
the reports of a serious and non-serious adverse event will be filled out in its various 
formats. Only cases marked by the researcher as "related" or according to the opinion 
of the sponsor 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 expression reasonable causal relationship means communicating that 
there is evidence or arguments to suggest a causal relationship. 
 
22. 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. 
 
23. STATISTICS 
 
Sample size 
We conducted a review of published articles regarding the use of medications in the 
treatment of bacterial conjunctivitis. We found three publications that are the following: 
 
 
1) “Gatifloxacin Ophthalmic Solution for Treatment of bacterial Conjunctivitis: 
Safety, Efficacy and Patient Perspective”. Clyde Schultz. En Ophthalmology and 
Eye Diseases. 2012:4 65-70. 
2) “Microbiological Efficacy of a New Ophthalmic Formulation of Moxifloxacin Dosed 
Twice-Daily for Bacterial Conujnctivitis”. Shachar Tauber et.al. En Adv Ther. 
(2010) 28(7):566-574. 
3) “Clinical use of gatifloxacin ophthalmic solution for treatment of bacterial 
conjunctivitis”. Lorenzo J. Cervantes y Francis S. Mah. En Clinical 
Ophthalmology. 2011:5 495.502. 
 
The first of the publications referred to here (Clyde Schultz) is a review article that 
summarizes the findings regarding the use of gatifloxacin mainly as a treatment for 
bacterial conjunctivitis but does not give precise figures, it only says, for example, that 
the Effectiveness reported in an article made in China was around 93%. It is not an 
original article that gives specific results, but rather comments findings and issues an 
opinion regarding the convenience of using them as an effective and safe treatment for 
bacterial conjunctivitis. 
 
The second revised article (Schachar Tauber) is an original article. This is a multicentre 
study in which 1180 patients were recruited throughout the United States of America, 
who had a clinical diagnosis of bacterial conjunctivitis. . All patients were given a sample 


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prior to treatment and another at the end of treatment, which were sent to the clinical 
laboratory where standard methods of microbiology were used to isolate the biological 
specimens before and after the treatments. One group was treated with MOXI-AF and 
the other with placebo (vehicle) instilling in the conjunctival sac one drop twice a day for 
three days and the most important results of this investigation are summarized in Table 
1. 
 
The third article reviewed (Cervantes) describes other studies conducted to test 
gatifloxacin in two presentations: Zymar (0.3%) tested in 52 patients treated for three 
days vs. placebo (vehicle) tested in 48 patients and Zymaxid (0.5%) tested in 333 
patients for three days vs. placebo (vehicle) tested in 325 patients for three days. 
 
The results reported in these articles regarding efficacy can be summarized in Table 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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To calculate the sample size, we obtained the overall average of absolute efficacy for 
patients treated with some medication and for patients treated with placebo. For patients 
treated with medication, the absolute efficacy (total disappearance of bacteria in the post-
treatment culture) was 69.8% and for those treated with placebo it was 53.3%. The 
specific efficacy (disappearance of a specific bacterium that was present in the pre-
treatment culture) for the groups treated with some medication was 92.34% and for 
patients treated with placebo 66.12%. 
 
With these figures, we can calculate the sample size needed to detect that level of 
differences reported between patients with bacterial conjunctivitis treated with 
medication vs. patients treated with placebo. 
Annex 1 develops the calculations for the sample size necessary to detect the 
differences in the percentage of efficacy to eliminate bacteria from patients with bacterial 
Cuadro 1. Eficacia de medicamentos para erradicación de bacterias en infecciones
oculares (Conjuntivitis) reportada en publicaciones.
Tratamiento
Eficacia Absoluta
n
n
%
MOXI-AF1
424
316
74.53%
Placebo (Vehículo)1
423
237
56.03%
Zymar2
52
40
76.92%
Placebo (Vehículo)2
48
28
58.33%
Zymaxid2
333
193
57.96%
Placebo (Vehículo)2
325
148
45.54%
Tratamiento
Eficacia específica por bacteria
MOXI-AF1
Haemophilus influenzae
67
66
98.51%
Streptococcus pneumoniae
22
19
86.36%
Staphylococcus aureous
17
16
94.12%
Placebo (Vehículo)1
Haemophilus influenzae
52
31
59.62%
Streptococcus pneumoniae
18
9
50.00%
Staphylococcus aureous
15
12
80.00%
Zymar2
*
52
48
92.31%
Placebo (Vehículo)2
*
48
34
70.83%
Zymaxid2
*
333
301
90.39%
Placebo (Vehículo)2
*
325
228
70.15%
* Nota: La eficacia específica por bacteria en los estudios con Zymar y con Zymaxid no se
presenta para cada bacteria sino para la totalidad de bacterias que aparecieron en el cultivo
inicial y ya no aparecieron en el cultivo post-tratamiento.
Eficacia
Total ojos
1 Microbiological Efficacy of a New Ophthalmic Formulation of Moxifloxacin Dosed Twice-
Daily for Bacterial Conujnctivitis. Shachar Tauber et.al. En Adv Ther. (2010) 28(7):566-574.
2 Clinical use of gatifloxacin ophthalmic solution for treatment of bacterial conjunctivitis. 
Lorenzo J. Cervantes y Francis S. Mah. En Clinical Ophthalmology. 2011:5 495-502.


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conjunctivitis found in the articles reviewed between patients treated with any drug vs 
patients treated with placebo. The Fleiss formula is used for case-control studies. 
 
 
From the calculations made we can draw the following conclusions and 
recommendations. The average absolute efficacy found in the articles commented is 
almost 70% (69.8%) for patients treated with any medication and only 53.3% for patients 
treated with placebo (in this case vehicle was used as a placebo). According to the Fleiss 
formula for cases and controls, a sample of 147 cases per group assures us that if the 
differences that we are going to prove between the treatments is of that magnitude (69.8 
%% vs 53.3%) or greater, we will have a 80% probability that the statistical test that we 
apply to evaluate the differences will be statistically significant (Power or power of the 
sample), and on the other hand, if the differences between the treatments were not of 
that magnitude (the differences were of lesser magnitude ), when applying a statistical 
test on the results of a sample of 147 cases with minor differences to the ones presented, 
it will be not significant and the probability of this happening will be 0.95 (Reliability of 
the sample). 
 
 
In summary, to prove differences in the absolute efficacy of two treatments in which one 
has almost 70% absolute efficacy and the other of only 53.3%, a sample of 147 cases 
per group will be necessary to have a reliability of 95% and a 80% power. 
 
 
If instead of calculating the sample size with absolute efficiency we calculate it with the 
specific efficacy for specific bacteria, using the percentages that we obtained from the 
review of the articles published and that were 92.34% and 66.12% for patients treated 
with some medication and for those treated with placebo respectively, the sample 
according to the Fleiss formula for a 95% reliability and a power of 80% is 44 patients 
per group. 
 
 
We can suggest that the minimum sample should be 50 eyes per treatment group and if 
possible, it would be desirable that the sample per group could reach 150 cases per 
group. 
 
Of course, the theoretical calculations are a part of the sample size problem, the other 
part refers to the resources available. Given that 5 medications are going to be tested: 
Vigamoxi®, Zymar®, and PRO-157 in three posologies and probably a placebo group 
as long as this does not contravene ethical aspects, if the sample were 50 eyes per 
group, it would imply 250 or 300 cultures and studies of microbiology or PCR before the 
treatments and another at the end of them. If the sample increased to 150 eyes per 
group, then these figures would triple. In short, the theory indicates that an adequate 
sample to establish and confirm statistically differences in the magnitudes reported in 
other studies between drug treatments and placebo treatments should be approximately 
between 50 and 150 eyes. 
 
 
ANNEX 1. Calculation of sample size. 
 
 
 


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Fórmula de Fleiss para el cálculo del tamaño de muestra para proporciones.
"Statistical Methods for Rates and Proportions"   2a. Ed. Pp. 38-45
Wiley. 1981. EUA.
Casos y Controles.
r = Razón de:
Controles : Casos  =
1
:
1
1.00
P1 = Eficacia absoluta en el grupo tratado con algun medicamento.
0.6980
Q1 = 1 - P1
0.3020
P2 = Eficacia absoluta en el grupo tratado con placebo.
0.5330
Q2 = 1 - P2
0.4670
P = Proporción promedio ponderada de eficacia absoluta.
   (P1 + r * P2)
0.6155
        r  +  1
Q = 1 - P
0.3845
a= Nivel de significancia o probabilidad de error tipo 1
0.050
1-a/2= Percentil bilateral para el nivel de significancia asignado
0.975
Z1-a/2= Z0.975 de la distribución normal estandarizada que deja un area de
0.975 a la izquierda. Implica una confiabilidad del 95%
1.960
b= Probabilidad de error tipo 2
0.200
1-b= Percentil unilateral para la beta asignada
0.800
Z1-b= Z0.80 de la distribución normal estandarizada que deja un area de
0.80 a la izquierda. Implica un poder del 80%
0.842
m' = Tamaño de muestra
  ( z1-a/2
  (r + 1) *  P * Q     +   z1-b
r * P1 * Q1 + P2 * Q2  )2
r * (P2 - P1)2
  ( 1.960
(1.00+1) 0.62 * 0.38
 + 0.842
1.00 * 0.70 * 0.30 + 0.53 * 0.47  )2
1.00 (0.53 - 0.70 )2
m' =
m =
Tamaño de muestra corregido
   2 (r + 1)
2
m =
  0.25  m'  *
1 +
1
+

  m' * r * | P2 - P1 |
m =
Tamaño de muestra para el grupo de referencia (Controles):
m1=r*m
Tamaño de muestra para el grupo de estudio (Casos):
m2=m
147
147
147
P =
m' =
m' =
135.272


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Fórmula de Fleiss para el cálculo del tamaño de muestra para proporciones.
"Statistical Methods for Rates and Proportions"   2a. Ed. Pp. 38-45
Wiley. 1981. EUA.
Casos y Controles.
r = Razón de:
Controles : Casos  =
1
:
1
1.00
P1 = Eficacia específica en el grupo tratado con algun medicamento.
0.9234
Q1 = 1 - P1
0.0766
P2 = Eficacia específica en el grupo tratado con placebo.
0.6612
Q2 = 1 - P2
0.3388
P = Proporción promedio ponderada de eficacia específica
   (P1 + r * P2)
0.7923
        r  +  1
Q = 1 - P
0.2077
a= Nivel de significancia o probabilidad de error tipo 1
0.050
1-a/2= Percentil bilateral para el nivel de significancia asignado
0.975
Z1-a/2= Z0.975 de la distribución normal estandarizada que deja un area de
0.975 a la izquierda. Implica una confiabilidad del 95%
1.960
b= Probabilidad de error tipo 2
0.200
1-b= Percentil unilateral para la beta asignada
0.800
Z1-b= Z0.80 de la distribución normal estandarizada que deja un area de
0.80 a la izquierda. Implica un poder del 80%
0.842
m' = Tamaño de muestra
  ( z1-a/2
  (r + 1) *  P * Q     +   z1-b
r * P1 * Q1 + P2 * Q2  )2
r * (P2 - P1)2
  ( 1.960
(1.00+1) 0.79 * 0.21
 + 0.842
1.00 * 0.92 * 0.08 + 0.66 * 0.34  )2
1.00 (0.66 - 0.92 )2
m' =
m =
Tamaño de muestra corregido
   2 (r + 1)
2
m =
  0.25  m'  *
1 +
1
+

  m' * r * | P2 - P1 |
m =
Tamaño de muestra para el grupo de referencia (Controles):
m1=r*m
Tamaño de muestra para el grupo de estudio (Casos):
m2=m
44
P =
m' =
m' =
36.373
44
44


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Analyzed data set 
The data will be analyzed in two groups, one will be made up of the population evaluable 
by Intention to Treat (ITT) in which each of the variables is described, the ITT population 
will be constituted by all the recruited subjects who have received at least one dose of 
study treatment. 
Others will be the evaluable population Per Protocol (PP) which is the subset of ITT 
composed of all subjects without any major deviation from the protocol, in which the 
bivariate analysis will be performed. 
 
24. DIRECT ACCESS TO DATA / DOCUMENTS SOURCE 
The researcher will allow the monitors, the persons responsible for auditing, the 
representatives of the Ethics Committee, and the Competent Authorities to have direct 
access to the data / source documents. 
 
25. QUALITY CONTROL AND QUALITY ASSURANCE 
25.1 Supervision of the study 
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 requirements of the protocol. 
A meeting of researchers will be organized before the start of the study. 
 
The researcher will allow the monitor: 
- Inspect the site, facilities and materials used for the study, 
- Meet with all the members of your team that participate in the study, 
- See all documents related to the study, 
- Have access to the FRCs and that they are filled correctly, 
- Direct access to the source documents to compare the data contained there against 
the FRC data, 
- Verify that the study is carried out in compliance with the protocols and regulatory 
requirements. 
 
 If computerized medical records are used, the investigator should: 
- At the start of the study, print all medical records of all participants, 
- During the study, print in real time each of the data entries and each change to the 
data. 
 
The researcher will personally put the signature and date on the first page of the printout 
and indicate the number of pages. 
 At each monitor visit, the investigator will provide you with all the impressions of the 
medical records of the participants. The Principal Investigator will personally place a date 
and signature on every page of each printout and indicate on the first page the number 
of pages. 
If the computer system allows tracking of changes made to medical records to be used, 
the investigator will give the monitor at each visit an impression of the medical records 
of the participants and the records of the changes made. The researcher will personally 
place the date and signature on the first page of each printout, and the monitor will do 
so on all pages. The researcher and the monitor will put the number of pages on the first 
page. 
Study monitoring visits will be conducted at regular intervals, depending on the 
recruitment rate, under the arrangements between the investigator and the sponsor. All 
information related to these visits will be handled as strictly confidential. 
 


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25.2 Computerized medical record 
 
If computerized medical records are used and the computer system allows it, no change 
made to medical records by the investigator should hide the original information. The 
record should clearly indicate that a change was made and provide clear means to locate 
and read the above information. The researcher will save the data at regular intervals. 
 
The researcher must guarantee the security 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: 
- In the record of the study, all the impressions of the medical file signed and dated by 
him. 
- If the computer system allows it, the documentation of the changes made during the 
study to the medical records in the study file, 
- All original source documents (original of the specific exams, forms of informed consent, 
...). 
 
 
25.3 Audit - Inspection-Verification 
 
The investigator should be informed of the possibility of an audit being conducted during 
or after the end of the study. 
 
The investigator should be informed that the Competent Authorities may also perform an 
inspection or verification 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: 
- Inspect the site, the facilities and the material used for the study, 
- Meet with all the members of your team participating in the study, 
- Have direct access to the study data and source documents, 
- See all documents related to the study. 
 
If computerized medical records are used, the researcher undertakes to provide all 
source documents and impressions of the medical records of the participants, and if the 
computer system allows it, the record of the changes made during the study. 
 
 
 
 
 
 
 
 
 
 


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26.ÉTICA 
 
26.1 Research Ethics Committee 
 
The Principal Investigator will submit to the Research Ethics Committee the study 
protocol, informed consent, investigator's manual, materials to be delivered to the 
patient, recruitment materials, and the required documents in accordance with local 
requirements. 
The study will not start in the center without first having obtained the approval of the 
corresponding Research Ethics Committees, having complied with the local regulatory 
requirements, having obtained the signing of the confidentiality agreements, economic 
proposal and signature of the contract of each one of them. the main medical 
researchers. 
 
26.2 Realization of 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). 
26.3 Information for the subject and form of informed consent 
Informed consent must be obtained before the patient is given 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 will be in compliance with all applicable laws and regulations. 
The principal investigator (or a medical member of the site investigation team duly 
specified by the principal investigator in delegation of responsibilities format) will provide 
the prospective participant with all information regarding the characteristics of the study, 
its potential risks, benefits, objectives and procedures. of the same. This information will 
be in a language understandable to the subject, it will be explained to the patient that he 
has the right to interrupt his participation in the study at any stage, without affecting the 
relationship with the researcher and / or his future assistance. The informed consent will 
be put to the consideration of the possible participant; This 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 informed 
consent letter 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 doubts were clarified if they existed. 
If a patient is illiterate, the acceptance will be with his / her fingerprint, and in the event 
that the patient is not able to grant an informed written consent, a representative of the 
"legally authorized" patient can provide such consent. the subject 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 


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participant. The Investigator must document in the patient's medical history, the date on 
which he signed the informed consent. 
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. 
 
26.4 Modification to "informed consent" 
 
Any change to "informed consent" constitutes an amendment to this document and must 
be submitted for approval to the Research 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 obtaining the written approval of the 
Research Ethics Committee and having complied with local regulatory requirements, 
with the exception of an amendment that is required to eliminate an immediate danger 
to study patients. 
Each patient affected by the amendment must fill out, date and sign two originals of the 
new version. The patient will be given a signed original of the amendment and the 
researcher will keep the second original. 
 
 
27. DATA MANAGEMENT AND CONSERVATION OF RECORDS 
 
 
27.1 Data of the study 
 
The investigator or the designated person on your team will fill out the Case Report 
Format (FRC) as well as all other documents provided by the sponsor (for example, 
documents related to handling the treatment ...). 
 
 
27.2 Case Report Form (FRC) 
 
An FRC 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 to modify what was written by the subject 
of the study. 
 
The data capture in the researcher's site will be done by the researcher 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 FRC. 
 
All corrections to the data to the FRC must be made by the investigator or the designated 
person of your team in accordance with the instructions provided, as described below. 
To ensure the confidentiality and security of the data, user names and access codes will 
be used to restrict access to the system only to authorized personnel, whether resident 
within the researcher's, the sponsor's or third party's sites. 
The monitor should ensure that all the data in the FRC has been filled. After comparing 
the data against the source documents, the monitor will ask the researcher to make the 


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correction / clarification using clarifications, so that they are answered and closed as 
quickly as possible. 
 
 
27.3 Data management 
 
The data will be collected in the FRC, once having a copy of the FRC of each of the visits 
of each patient who has completed the study will be transcribed to a database, the 
database mask will coincide with the form of report of case and the data of each of the 
FRCs 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 discrepancies 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. 
 
 
27.4 Archive 
 
The investigator will keep all the information related to the study for at least 10 years 
after the completion of the study. 
 
 
28. OWNERSHIP OF THE RESULTS - PUBLICATION POLICY 
 
Laboratorios Sophia S.A de C.V., acting as the sponsor of the study, assumes full 
responsibility for its function and retains exclusive ownership rights to the results of the 
study, which may be used in the manner it deems appropriate. 
Because the study is multicentric, the first publication should be made 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 prior written agreement is given by Laboratorios Sophia S.A. of C.V. 
 
Any project of publication and / or communication related to the study and / or related to 
the results obtained during the study or after the termination of the study 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. 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, from the date on which the project is received. 
 
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 date of registration. 
 
 
 
 


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29. ADMINISTRATIVE CLAUSES 
 
29.1 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. 
 
29.2 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 noted. 
 
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 met the requirements, and that the 
document of the amendment was signed, except when a measure is required to eliminate 
an immediate danger to the patients in the study. 
 
In addition, the substantial amendment must be submitted to the Competent Authorities 
in accordance with local regulatory requirements. 
 
29.3 Final report of the study 
 
The report of the study will be elaborated by Laboratorios Sophia S.A de C.V. After 
completing the statistical analysis of the data, a final report will be designed, according 
to the BCH of ICH. 
 
29.4 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 carry out the study, 
- Obtain any authorization to carry out the study and / or the import license for the 
treatment or treatments administered that might be required by the local authorities 
before starting the study (if it is international). 
 
30. 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 on paper and stored on the computer, are 
solely for use related to their activities such as sponsor of clinical studies, in accordance 
with Good Clinical Practices. The researcher accepts that he / she and the members of 
his team will use the information only within the framework of this study, to carry out the 
protocol. This agreement is mandatory as long as the confidential information has not 
been disclosed to the public by the sponsor. The protocol of the clinical study provided 
to the investigator may be used by the researcher and by his colleagues to obtain the 


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informed consent of the patients for the study. 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 S.A. of C.V., except to the representatives of the Competent 
Authorities, and only by request of the same. 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 selection log of the 
subjects as well as the identification and enrollment list of each of the patients. 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 patient could participate in the study (through assessment of the 
patient's medical history during a visit or review of the medical record.) 
 
31. 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 Delegation format of 
Responsibilities. 
 
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. 
 
32. Documentation to be delivered to the sponsor 
 
The researcher undertakes, before the start of the study: 
- To provide your 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 that of his or her collaborators or work team, 
- Copy of Academic Certifications (undergraduate and postgraduate degrees and federal 
professional cedulas) 
- If you apply a copy of the operation notice (when it is a private practice). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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33. 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. 
 
The Declaration must be read in its entirety and each of the paragraphs that comprise it 
must not be applied without considering all the other relevant paragraphs. 
 
2. Although the Declaration is intended primarily for physicians, the AMM encourages 
other participants in medical research involving human subjects to adopt these 
principles. 
 
3. The doctor's duty to promote and safeguard the health of patients, including those who 
participate in medical research. The knowledge and conscience of the doctor are 
dedicated to the fulfillment of this duty. 
 
4. The Geneva Declaration of the AMM forces physicians with the words, "the health of 
my patient 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 patient when 
he provides medical attention. " 
 
5. Medical progress is based on research, which must ultimately include studies on 
human beings. The populations that are underrepresented in medical research should 
be given access to participate in the research. 
 
6. In medical research involving human beings, the well-being 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.) 
 
7. The main objective of medical research with human beings is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the most current 
interventions must be evaluated continuously by means of research into their safety, 
effectiveness, efficiency, accessibility and quality. 
 
8. In medical practice and in medical research, most interventions involve risks and 
burdens. 
 
9. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are especially 
vulnerable and require special protection. These populations include those who can not 
give or withhold their consent on their own and those who may be susceptible to coercion 
or undue influence. 
 
10. Physicians should consider ethical, legal and normative norms and standards for 
research with humans in their own countries, as well as applicable international norms 
and standards. No ethical, legal or regulatory requirements, national or international, 
shall reduce or eliminate any of the protection for the research subjects established in 
this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL INVESTIGATIONS 
 
11. It is the duty of physicians who participate in medical research to protect the life, 
health, dignity, integrity, right of self-determination, privacy, and confidentiality of the 
personal information of the research subjects. 
 
12. Medical research with human beings must conform to generally accepted scientific 
principles, based on a perfect knowledge of the scientific literature, other relevant 
sources of information, and on correct experimentation in the laboratory, and when 
relevant in animals. The welfare of the animals used for research purposes must be 
respected. 
 
13. Appropriate precautions should be taken when conducting medical research that may 
harm the environment. 
 
1. The design and execution 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 participating in the study. research. 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.) 
 
 
2. The protocol in the investigation 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. 
 
3. Medical research involving human beings should only be carried out by individuals 
with the appropriate scientific qualifications and training. Research on patients or 
subjects in healthy subjects 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. 
 
4. 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. 
 
5. Any 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 that 
participate in the research, compared to the benefits provided for them and for other 
affected individuals or communities. for the condition under investigation. 
 
6. Clinical studies should be recorded in a database with access to the public before 
recruiting the first subject. 
 
7. 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. 
 
8. Medical research with human beings can only be carried out if the importance of the 
objective exceeds the risks and burdens inherent to the subjects under investigation. 
 
9. 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.) 
 
 
 
10. 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. 
 
11. In medical research with human beings, 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, granted freely and 
preferably in writing. If it can not be expressed in writing, the unwritten consent must be 
formally documented and witnessed. 
 
In the case of medical research that uses identifiable human material or data, physicians 
should normally seek consent to collect, analyze, store and / or reuse samples. There 
may be situations in which it is impossible or impractical to obtain consent for such an 
investigation, or that could imply a threat to the validity of the investigation. In such 
situations, the investigation may be carried out only after it has been submitted to the 
research ethics committee for approval. 
 
26. When trying to obtain "Information for the patient and form of informed consent" for 
participation in a research study, the doctor should be especially cautious if the possible 
subject has a relationship of dependence with the doctor or could give his consent under 
duress In such situations, informed consent should be sought by a qualified individual 
who is completely independent of this relationship. 
 
27. In the case of a possible research subject who is incompetent, the doctor will try to 
obtain the informed consent of a legally authorized representative. These individuals 
should not be included in a research study if there is no likelihood of benefit to them, 
unless it is intended to promote the health of the population represented by the potential 
subject and the research can not be carried out with competent persons, and research 
involves only risks and minimum burdens. 
 
28. When a potential research subject, who considers himself incompetent, can give his 
consent to participate in the investigation, the doctor must also seek the consent of the 
legally authorized representative. The denial of the possible subject must be respected. 
 
 
 
 
 
 
 
 


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Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
 
29. Research involving individuals who are physically or mentally disabled to give their 
consent, for example unconscious patients, may be performed only if the physical or 
mental condition that prevents their informed consent is 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 can not 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. 
 
30. All authors, publishers and printers have ethical obligations regarding the publication 
of research results. The authors have the duty to make publicly available the results of 
their research with human beings and will be responsible for the integrity and accuracy 
of their reports. They must adhere to the accepted guidelines for the ethical report. 
Negative and inconclusive results should be published, as well as positive results, or 
made publicly available. The publication should include sources of funds, institutional 
affiliations and conflicts of interest. Reports of an investigation that are not in accordance 
with the principles of this Declaration shall not be accepted for publication. 
 
Appendix 1: Declaration of Helsinki of the World Medical Association (cont.) 
 
 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL ATTENTION 
 
31. The physician may combine medical research with medical care only to the extent 
that the research is justified by its possible preventive, 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 patients who serve as research subjects. 
 
32. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best intervention currently tested, except in the following 
circumstances: 
• It will be acceptable to use a placebo or not to administer treatment when there is no 
currently proven intervention; or 
• When for methodological and scientific reasons the use of placebo is necessary to 
determine the efficacy or safety of an intervention, and patients who are given placebo 
or no treatment are not at risk of serious or irreversible damage. Care should be taken 
to avoid abuse of this option. 
 
33. At the end of the study, patients 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. 
 
 
 
 


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34. The physician must fully inform the patient which aspects of the care are related to 
the investigation. The refusal of the patient to participate in a study, or the decision of 
the patient to withdraw from the study should never interfere with the patient-doctor 
relationship. 
 
35. In the treatment of a patient, when there are no proven interventions or have been 
ineffective, the doctor, after seeking expert advice and with the informed consent of the 
patient 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: Format for Pregnancy Follow-up 
 
Any fetal exposure to the product or products of the study triggers a procedure for 
monitoring pregnancy, especially to identify: 
- cases in which pregnancy occurs unexpectedly, when an interaction with the method 
of contraception used is suspected (oral contraceptives, especially) 
- any pregnancy termination during the study: either spontaneous or induced abortion, 
regardless of the reason, 
- birth of a product, infant with deformations or abnormal, during or after the study. The 
latter always constitutes a serious adverse event. 
 
The first page of the format for pregnancy follow-up should be filled out by the researcher 
starting from the beginning of the pregnancy and forward, if necessary with the help of 
other doctors who attended to the patient. The second sheet will be filled later when the 
pregnancy has ended, with the help of the researcher, other doctors, obstetricians, 
midwives, etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2. Format for Pregnancy Tracking (cont.) 
 
 
A - INFORMANT 
 
Name:  
 
 
Population:  
 
 
Country: 
 
Telephone No.:  
 
Center No.: 
 
 
 
B - INFORMATION RELATED TO PREGNANT WOMEN 
First Name: ...  
Last Name: ...  
 
Date of Birth (DD-MM-YYYY): 
Participant No.:  
 
 
       Last menstruation date (DD-MM-YYYY): 
• Positive pregnancy test         Date (DD-MM-YYYY): 
 
Exposure of the patient to the study product (1 
 
No. Protocol: 
Dosage *:  
 
 
 
 
Indication: 
Via: 
 
Date taken first (DD-MM-YYYY):  
 
Date last taken (DD-MM-YYYY): 
 
Concomitant medications (including oral contraceptives) 
 
 
 
 
 
 
 
First name 
Daily dose 
First date taken 
Date taken last ** 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substances taken by recreation by the pregnant woman 
Tobacco: cigarettes / day: Alcohol: 
 
Illicit drugs: 
 
Obstetric history 
 
Pregnancy or previous pregnancies: • Yes • No 
 
If the answer is yes: number of pregnancies  
 
Number of deliveries at term: 
 


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Appendix 2. Format for Pregnancy Tracking (cont.) 
 
 
 
Number of premature births: Number of abortions: 
 
• Previous fetal / neonatal abnormalities 
 
  Specify: 
 
• Complications during previous pregnancies 
  Specify: 
 
Medical history of the pregnant woman 
 
 
 
 
 
 
 
Date of filling: 
 
First name: 
 
 
 
* In case of dose modification during the study, specify the dates of the first and last dose 
of each dose of the study product. 
** Report NA (Not Applicable) if it is in progress 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Format for Pregnancy Tracking (Cont.) 
 
 
Protocol No.: Center No.: 2/2 
Participant No.: 
 
 
 
C - RESULT OF PREGNANCY 
 
Complications of the mother 
• High blood pressure:  
 
• Diabetes: 
• Infection: 
 
 
            • Other       Specify: 
 
 
Other medications administered during pregnancy 
First name 
Daily dose 
First date taken 
 
Date taken last   
 
Pregnancy monitoring (relevant examinations / biological results) 
 
 
Result 
• Live birth           Proceed with section D - NEONATO INFORMATION 
• Spontaneous abortion / dead birth   
 Date (DD-MM-YYYY): 
Were congenital anomalies detected? • No • Yes      Specify: 
 
• Elective termination   
Date (DD-MM-AA) 
 
 
 
• Therapeutic termination          Date (DDMMAA): 
Results of fetal tests and reason for termination: 
 
 
D - NEONATO INFORMATION 
 
Date of birth (DD-MM-YYYY):  
Gestational age at birth:  
weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Physical examination at birth: 
• Dysmorphic features were not identified 
• Minor anomalies   
 
    Specify: 
• Major malformations 
• Syndrome / diagnosis 
   Specify: 
• Other important findings         Specify: 
Apgar Ratings:  
1min:   
5min: 
 
 
 
Finish date: 
 
First name: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3. Report Format of Serious Adverse Events 
 
 
 
 
 
 
 


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Appendix 3: Report Format of Serious Adverse Events (Cont.) 
 
 
 
 
 
 
 
 
 


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Appendix 4. Medication Inventory and Accounting Format 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix. 5 Humidity and temperature record of medication for clinical studies. 
 
 
 
 
 


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34. REFERENCES 
 
i. 
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