Clinical trial NCT04111965
Conditions: Dry Eye
Keywords: Dry eye propylene glycol
Sponsor: Laboratorios Sophia S.A de C.V.
Start date: 2020-12-01; Completion date: 2021-12-10
Enrollment: 126 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study design:

Phase I-II clinical trial, comparative, non-inferiority with active control, parallel groups, double blind with randomisation. Safety analysis when completing the visits of the first 12 subjects of the Nanodrop® group, if there are less than 20% of unexpected Events (EA), related to the research product, recruitment is continued until the sample is completed for efficacy analysis

objectives Security: Evaluate the safety of the ophthalmic application of Nanodrop® by quantifying the incidence of unexpected Adverse Events (EA) related to the research product (PI).

Effectiveness: Demonstrate the non-inferiority of Nanodrop® compared to Systane® Balance, in the efficacy of the treatment of patients with dry eye, by means of the Ocular Surface Disease Index (OSDI).

Hypothesis

Security:

H0 = Nanodrop® is safe in its ophthalmic application as it presents an incidence of unexpected adverse events related to the research drug, less than 20% of the population of Nanodrop® safety group.

H1 = Nanodrop® is not safe in its ophthalmic application, as it presents an incidence of unexpected adverse events related to the research drug, exceeding 20% of the population of Nanodrop® safety group.

Effectiveness:

H0 = Nanodrop® is lower than Systane® Balance by more than 5 points in the OSDI test score.

H1 = Nanodrop® is lower than Systane® Balance by 5 points or less in the OSDI test score.

Number of subjects: n = 126 evaluable subjects 63 evaluable subjects per group (both eyes).

Main inclusion criteria: Dry eye diagnosis

Duration of intervention treatment: 28 days Approximate duration of the subject in the study: 35 days

Detailed description:

Arms: arm 1: \- Nanodrop®. 0.6% propylene glycol. Ophthalmic emulsion Laboratorios Sophia, S.A. from C.V. Route of administration: Ophthalmic. arm 2: * Systane® Balance. 0.6% propylene glycol. Ophthalmic emulsion Alcon Laboratories, Inc.
* Route of administration: Ophthalmic.
Interventions: intervention 1: Nanodrop® intervention 2: Systane Balance
Intervention descriptions: intervention 1: minimum to meet 1 drop 4 times a day, both eyes intervention 2: minimum to meet 1 drop 4 times a day, both eyes

Protocol documents:
Prot_000.pdf: 
 
  
 
Clinical study title: 
Phase I-II clinical study to compare the safety 
and efficacy of Nanodrop® versus Systane® 
Balance in the treatment of patients with dry 
eye 
Study number: SOPH176-1218/I-II 
Protocol version: 1.0 
Version date: 11 de diciembre de 2018 
This protocol has been developed in accordance with the principles of 
the Declaration of Helsinki and will be carried out in accordance with 
Good Clinical Practices and in compliance with ICH guidelines and current 
local legislation. 
Sponsor: Sophia Laboratories, SA de CV 
 
 
 


 
 


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Content 
Content 
Contents  ............................................................................................................................................. 1 
Index of charts, tables and figures  ................................................................................................. 5 
Those responsible for study  ............................................................................................................... 6 
Signature Page  .................................................................................................................................... 7 
From sponsor  ................................................................................................................................. 7 
Researcher Agreement  ................................................................................................................... 8 
List of abbreviations  ........................................................................................................................... 9 
1.  Summary  .................................................................................................................................. 10 
1.1  
Synopsis  ............................................................................................................................ 10 
1.2  
Study diagram ................................................................................................................... 14 
1.3  
Study schedule  ................................................................................................................. 15 
2.  Introduction and Background  .................................................................................................. 16 
2.1  
Theoretical framework  ..................................................................................................... 16 
2.2  
Background on the product under study  ......................................................................... 20 
2.2.1  
Pharmacology of the investigational product  .......................................................... 20 
2.2.2  
Efficacy of the investigational product  ..................................................................... 20 
2.2.3  
Safety of the investigational product  ....................................................................... 20 
2.2.4  
Summary of the pharmaceutical development of the investigational product  ....... 20 
2.3  
Background on the research  ............................................................................................ 21 
2.3.1  
From research question  ........................................................................................... 21 
2.4  
Risk-benefit assessment  ................................................................................................... 21 
2.4.1  
Known potential risks  ............................................................................................... 21 
2.4.2  
Known potential benefits  ......................................................................................... 21 
2.5  
Problem statement  .......................................................................................................... 21 
2.6  
Justification  ...................................................................................................................... 22 
3.  Objectives and hypotheses  ...................................................................................................... 23 
3.1  
Primary objectives  ............................................................................................................ 23 
3.1.1  
Primary security objective  ........................................................................................ 23 
3.1.2  
Primary efficacy objective  ........................................................................................ 23 
3.2  
Secondary objectives  ........................................................................................................ 23 


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3.2.1  
Secondary security objective  .................................................................................... 23 
3.2.2  
Secondary efficacy objectives  .................................................................................. 23 
3.3  
Exploratory objectives  ...................................................................................................... 23 
3.4  
Hypothesis  ........................................................................................................................ 23 
3.4.1  
Security hypothesis  .................................................................................................. 23 
3.4.2  
Null hypothesis  ......................................................................................................... 24 
4.  Study design  ............................................................................................................................. 25 
4.1  
Design Overview  ............................................................................................................... 25 
4.2  
Justification of the study design  ....................................................................................... 25 
4.3  
Expected duration  ............................................................................................................ 25 
5.  Study population  ...................................................................................................................... 26 
5.1  
Eligibility criteria  ............................................................................................................... 26 
5.1.1  
Inclusion criteria  ....................................................................................................... 26 
5.1.2  
Exclusion criteria  ...................................................................................................... 26 
5.2  
Criteria for elimination and substitution of subjects  ....................................................... 27 
5.2.1 Elimination criteria  .......................................................................................................... 27 
5.3.1 Substitution of subjects  ................................................................................................... 27 
5.3  
Lifestyle Considerations  ................................................................................................... 27 
5.4  
Scrutiny failures  ................................................................................................................ 28 
5.5  
Recruitment and retention strategies  .............................................................................. 28 
5.6  
Procedure in case of loss of tracking  ................................................................................ 28 
5.7  
Subject Identification  ....................................................................................................... 29 
6.  Investigational Product  ............................................................................................................ 30 
6.1  
Managed Products  ........................................................................................................... 30 
6.1.1  
Investigational Product  ............................................................................................ 30 
6.1.2  
Reference product  .................................................................................................... 30 
6.1.3  
Dosage of investigational products  .......................................................................... 30 
6.2  
Storage and handling of investigational products at the study center  ............................ 31 
6.3  
Concomitant treatments and medications not authorized during the study  .................. 31 
6.4  
Procedure for monitoring and measuring adherence ...................................................... 32 
6.5  
Strategies to improve adherence  ..................................................................................... 33 
7.  Methods and procedures of the study  ..................................................................................... 34 
7.1  
From the research center  ................................................................................................. 34 


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7.2  
Clinical study registration  ................................................................................................. 34 
7.3  
Randomization and blinding  ............................................................................................. 34 
7.3.1  
Opening the cecum  .................................................................................................. 35 
7.4  
Outcome variables  ........................................................................................................... 35 
7.4.1  
Primary outcome variables  ...................................................................................... 35 
7.4.2  
Secondary outcome variables  .................................................................................. 35 
7.4.3  
Exploratory outcome variable  .................................................................................. 35 
7.4.4  
Definition of variables, methods and scales to be used for measurement  ............. 36 
7.5  
Study  ................................................................................................................................. 40 
7.5.1  
Description of activities per visit  .............................................................................. 40 
7.5.2  
Unscheduled follow-up visits  ................................................................................... 42 
7.6  
Data Collection  ................................................................................................................. 42 
7.6.1  
Source documents  .................................................................................................... 42 
7.6.2  
Electronic forms of data collection  .......................................................................... 42 
7.6.3  
File  ............................................................................................................................ 43 
8.  Evaluation and management of adverse events  ...................................................................... 44 
8.1  
Regulation and standards on adverse events  .................................................................. 44 
8.2  
Definition of adverse event  .............................................................................................. 44 
8.3  
Definitions relevant to the classification of adverse events  ............................................ 44 
8.4  
Researcher Responsibilities  .............................................................................................. 45 
8.4.1  
Recording of adverse events in the electronic case report form  ............................. 45 
8.4.2  
Monitoring of adverse events  .................................................................................. 47 
8.4.3  
Procedures for a serious adverse event  ................................................................... 47 
8.4.4  
Causality Assessment  ............................................................................................... 48 
8.5  
Unanticipated Problems  ................................................................................................... 50 
8.5.1  
PNA Report  ............................................................................................................... 50 
9.  Study monitoring  ...................................................................................................................... 51 
9.1  
Monitoring of study centers  ............................................................................................. 51 
9.2  
Audit and quality control  .................................................................................................. 51 
9.2.1  
Pre-study audit  ......................................................................................................... 52 
9.2.2  
Audit during the conduct of the study  ..................................................................... 52 
10.  
Statistical analysis  ................................................................................................................. 53 
10.1  Data Analysis  .................................................................................................................... 53 


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10.1.1  
Statistical analysis  ..................................................................................................... 53 
10.1.2  
Data interpretation ................................................................................................... 53 
10.1.3  
Procedure for handling missing data  ....................................................................... 54 
10.1.4  
Deviations from the statistical analysis plan  ............................................................ 54 
10.1.5  
Subjects included in the analysis  .............................................................................. 54 
10.2  Sample size calculation ..................................................................................................... 54 
10.2.1  
Number of subjects calculated  ................................................................................. 54 
10.2.2  
Justification of the sample calculation  ..................................................................... 55 
11.  
Ethical considerations  .......................................................................................................... 56 
11.1  Approval of committees  ................................................................................................... 56 
11.2  Amendments to Protocol  ................................................................................................. 56 
11.3  Early termination of the study  ......................................................................................... 57 
11.4  Informed consent  ............................................................................................................. 58 
11.4.1  
Obtaining  .................................................................................................................. 58 
11.4.2  
Special Considerations  ............................................................................................. 59 
11.4.3  
Modifications to informed consent  .......................................................................... 59 
11.5  Confidentiality  .................................................................................................................. 59 
11.6  Conflict of interest  ............................................................................................................ 60 
11.6.1  
Declaration of interests  ............................................................................................ 60 
11.7  Access to information  ....................................................................................................... 60 
11.8  Ancillary and post-study care  ........................................................................................... 60 
12.  
Biosecurity aspects  ............................................................................................................... 61 
13.  
Publication Policy  ................................................................................................................. 62 
13.1  Final Report  ...................................................................................................................... 62 
13.2  Communication of results  ................................................................................................ 62 
13.3  Publication of results  ........................................................................................................ 62 
14.  
Financing and insurance  ....................................................................................................... 63 
14.1  Compensation to Study Participants  ................................................................................ 63 
14.2  Insurance for study participants ....................................................................................... 63 
15.  
Annexes  ................................................................................................................................ 64 
15.1  OSDI  .................................................................................................................................. 64 
67 CTO format 65 


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Index of tables, charts and figures 
Table 1. Triage questions  ................................................................................................................. 19 
Table 2. Stages of dry eye treatment  ............................................................................................... 19 
 
Table 1. Study leaders  ........................................................................................................................ 6 
Table 2. Operational definition of variables  ..................................................................................... 36 
Table 3. Karch and Lasagna algorithm modified by Naranjo  ........................................................... 49 
 
Figure 1. Administrative structure  ..................................................................................................... 6 
Figure 2. Dry eye classification  ......................................................................................................... 17 
Figure 3. Diagnosis and management of dry eye  ............................................................................. 18 
Figure 4. Ocular Staining Rating SICCA  ............................................................................................. 40 
Figure 5. Adverse event care  ............................................................................................................ 47 
 
 
 


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Study leaders 
The administrative structure of the sponsoring party, corresponding to Laboratorios Sophia, SA de 
CV, is shown in Table 1Study leaders 
Function 
Name/Contact 
Membership ¥ 
Medical 
Director of the 
study 
  
 
 
Director of the 
study 
 
 
Clinical Team 
 
 
Clinical Team 
 
 
Clinical Team 
 
 
Employees of Laboratorios Sophia, SA de CV Av. Paseo del Norte No. 5255, Col. Guadalajara Technology Park, 
Guadalajara-Nogales Highway Km13.5 CP 45010 Zapopan, Jalisco, Mexico Tel +52 (33) 3000 4200 
Table 1Study leaders 
 
Figure 1Administrative structure 
 
Blind 
Project 
Leader 
Clinical Study 
Director 
Medical Director of 
the study 
Startup 
Specialist 
Blinded 
clinical 
Medical 
Editor/ 
Medical 
Monitor 
Biostatistics 
Logistics 
Coordinator 
Logistics 
Assistant 
Safety 
Pharmacolog
Clinical team 


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Signature page 
From the sponsor 
Name: 
 
 
Signature 
Qualification: 
 
Medical Director of the study 
Date 
 
Name: 
 
 
Signature 
Qualification: 
 
Director of the study 
Date 
 
Name: 
 
 
Signature 
Qualification: 
 
Author of the protocol 
Date 
 
 
 


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Researcher Agreement 
I agree to conduct this clinical study according to the design and guidelines of this protocol, adhering 
to the provisions of this protocol. I agree to conduct the study in accordance with accepted 
standards of Good Clinical Practice. I agree to report all information and data in accordance with the 
protocol, particularly any adverse events. I also agree to manage clinical supplies provided by the 
sponsor strictly in accordance with this protocol. I understand that the information that identifies 
me may be used by the sponsor. Because the information contained in this protocol and the 
Investigator's Manual is confidential, I understand that sharing it with any third party not involved 
in the approval, supervision, or conduct of the study is prohibited. I will ensure that necessary 
precautions are taken to protect the information from loss, inadvertent disclosure, or access by 
unauthorized parties. 
Name: 
 
 
Signature 
Qualification: 
 
 
Date 
Name of the center: 
 
 
 
Geographic location (city/state/country) 
 
 
 
 
 
 


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List of abbreviations 
av 
Visual acuity 
CEI 
Research Ethics Committee 
COFEPRIS 
Federal Commission for the Protection against Sanitary Risks 
CTO 
Ocular staining grading 
IUD 
Intrauterine device 
EA 
Adverse event 
EEP 
Punctate epithelial erosion 
THAT 
Ocular surface disease 
FCI 
Informed consent form 
FDA 
United States Food and Drug Administration 
FERC 
Electronic Case Report Form 
IC 
Confidence interval 
IP 
Principal Investigator 
MAVC 
Best corrected visual acuity 
OD 
Right eye 
WHO 
World Health Organization 
YOU 
Left eye 
OSDI 
Ocular Surface Disease Index 
PNA 
Unanticipated problems 
PI 
Research products 
QID 
Four times a day 
RNEC 
National Registry of Clinical Trials 
SICCA 
Sjögren's International Clinical Collaboration Alliance 
TEA 
Evaluation time 
TFOS DEWS II 
Tear Film and Ocular Surface Societies Dry Eye Workshop II 
TRPL 
Tear film break-up time 
TRPL-NI 
Non-invasive tear film break-up time 
 
 
 
 


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1. Summary 
1.1 Synopsis 
Title of the study: 
Phase I-II clinical study to compare the safety and efficacy of Nanodrop® versus Systane® 
Balance in the treatment of patients with dry eye 
Study number: 
SOPH176-1218/I-II 
Creation date: 
December 11, 2018 
Protocol version: 
1.0 
Version date: 
11-dic.-18 
Therapeutic indication: 
 Lubricante ocular 
Use: 
 Ojo seco 
Estimated duration of the study (from the first visit 
of the first patient to the preparation of the final report) : 
11 meses 
Development phase: 
 I-II 
Goals: 
Security: 
To evaluate the safety of ophthalmic application of Nanodrop® by quantifying the incidence of 
unexpected Adverse Events (AEs) related to the investigational product (IP). 
Effectiveness: 
To demonstrate the non-inferiority of Nanodrop® compared to Systane® Balance in the treatment 
efficacy of patients with dry eye, using the OSDI (Ocular Surface Disease Index) test score. 
Hypothesis: 
Security: 
H 0 =Nanodrop® is safe in its ophthalmic application, presenting an incidence of unexpected AEs, 
related to the PI less than 20% of the population of the Nanodrop® safety group 
H 1 = Nanodrop® is not safe for ophthalmic application, as it presents an incidence of unexpected 
AEs related to the PI greater than 20% of the population in the Nanodrop® safety group. 
Effectiveness: 
H 0 = Nanodrop® is inferior to Systane® Balance by more than 5 points on the OSDI test score 
H 0 : µ A - µ B > δ 
H 1 = Nanodrop® is inferior to Systane® Balance by 5 points or less on the OSDI test score 
H 1 : µ A - µ B ≤ δ 
Study design: 
Phase I-II, comparative, non-inferiority, active-controlled, parallel-group, double-blind, 
randomized clinical trial. Safety analysis is performed upon completion of the first 12 subjects in 
the Nanodrop® group. If fewer than 20% of unexpected adverse events (AEs) related to the 
investigational product occur, recruitment continues until the sample size for the efficacy analysis 
is complete. 
Number of subjects: 
n= 126 evaluable subjects 
63 evaluable subjects per group (both eyes). 
Main inclusion criteria: 
Diagnóstico de ojo seco 
Selection criteria : 
 


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Inclusion criteria: 
- 
Have the ability to voluntarily grant signed informed consent 
- 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures 
- 
Be willing to modify your lifestyle activities. See 5.3 Lifestyle considerations 
- 
Be of age 
- 
Women of childbearing potential must ensure continued use (started ≥ 30 days prior to 
signing the Informed Consent Form [ICF]) of a hormonal contraceptive method or 
intrauterine device (IUD) during the study period. 
- 
Present diagnosis of dry eye, defined by: 
o OSDI ≥ 13 points 
+ 1 of the following: 
▪ 
Corneal staining with more than 5 sites 
▪ 
Conjunctival staining with more than 9 sites 
▪ 
Tear film break-up time < 10 seconds 
 
Exclusion criteria: 
- 
For women: be pregnant, breastfeeding, or planning to become pregnant during the 
study period. 
- 
Having participated in another clinical research study ≤ 30 days prior to the screening 
visit. 
- 
Having previously participated in this study. 
- 
Present a Best Corrected Visual Acuity (BCVA) of 20/200 or worse in either eye. 
- 
Present an additional ophthalmological diagnosis of: 
o Allergic, viral or bacterial conjunctivitis. 
o Anterior blepharitis. 
o Demodex. 
o Parasitic eye infections. 
o Unresolved ocular trauma. 
o Healing diseases of the ocular surface. 
o Corneal or conjunctival ulcers. 
o Filamentous keratitis. 
o Neurotrophic keratitis. 
o Bullous keratopathy. 
o Neoplastic diseases of the ocular surface or annexes. 
o Diseases with fibrovascular proliferations on the conjunctival and/or corneal 
surface. 
o Diseases of the retina and/or posterior segment that require treatment or 
threaten the visual prognosis. 
o Glaucoma. 
- 
Have dry eye management that requires implementation of Stage 2 treatments from the 
TFO DEWS II (Tear Film and Ocular Surface Societies Dry Eye Workshop II) 
recommendations for the treatment and staged management of Table 2 
- 
Have a history of drug addiction or dependence, currently or within the last two years 
prior to signing the FCI. 
- 
Have a history of ocular surgical procedures within the last 3 months prior to signing the 
FCI. 


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- 
Wear soft or hard contact lenses. You may be admitted if you can discontinue use of 
contact lenses during the study. You must not wear contact lenses for 15 days prior to 
enrollment. 
- 
Having another medical condition, acute or chronic, that, in the opinion of the 
investigator, could increase the risk associated with participation in the study or the 
administration of the investigational product, or that could interfere with the 
interpretation of the study results. 
- 
Have a known hypersensitivity to the components of the investigational products. 
- 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is an employee of the research site or the sponsor and who is directly involved 
in this study. 
Research Products (RP): 
Investigational product, dosage and route of administration: 
- 
Nanodrop®. Propilenglicol 0.6%. Emulsión oftálmica.Laboratorios Sophia, S.A. de C.V. 
- 
Posology:mínima a cumplir de 1 gota 4 veces al día, ambos ojos. 
- 
Route of administration:Oftálmica. 
Comparator product, dose and route of administration: 
- 
Systane® Balance. Propilenglicol 0.6%. Emulsión oftálmica.Alcon Laboratories, Inc. 
- 
Posology:mínima a cumplir de 1 gota 4 veces al día, ambos ojos. 
- 
Route of administration:Oftálmica. 
Duration of treatment: 
28 días 
Approximate duration of the subject in the 
study: 
35days 
Evaluation criteria: 
Efficacy variables: 
Primary efficacy outcome variable: 
o OSDI Test Score (Evaluation Time [ET]: day 29). 
Secondary efficacy outcome variables: 
o Changes in best corrected visual acuity (BCVA) (TE: day 8 and 29). 
o Changes in fluorescein tear film break-up time (TRPL) (TE: day 8 and 29) 
o Corneal fluorescein staining changes (TE: day 8 and 29). 
o Changes in conjunctival staining with lissamine green (TE: day 8 and 29). 
Security variables: 
Primary safety outcome variable: 
o Incidence of unexpected AEs related to the PI (TE: day 8 and 29). 
Secondary safety outcome variable: 
o Incidence of expected AEs (TE day 8 and 29) 
Exploratory outcome variable: 
o Average number of applications performed daily 
Statistical methodology: 
Data will be expressed as measures of central tendency: mean, standard deviation, and ranges 
for quantitative variables. Qualitative variables will be presented as frequencies and percentages. 
Statistical analysis will be performed using the Student t test or the Mann-Whitney U test (if 


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applicable) for quantitative variables to determine the difference between groups. Differences 
between qualitative variables will be analyzed using the X 2 (Chi-square) test or Fisher's exact test. 
A 95% CI will be considered for non-inferiority criteria based on the study objectives, with an α < 
0.05 considered significant. 
 


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1.2 Study diagram 
Obtaining informed consent. Compliance with 
all selection criteria. Obtaining baseline values. 
N= 24. 
Arm 
Nanodrop® 
N=12 
Brazo 
Systane® Balance 
N=12 
Random assignment 
Informed consent obtained. All selection 
criteria met. Baseline values obtained. N=102. 
Arm 
Nanodrop® 
N=51 
Brazo 
Systane® Balance 
N=51 
Random assignment 
Safety Analysis 
Less than 20% of 
unexpected AEs 
related to the PI in 
the Nanodrop 
group? 
yes = Continue 
recruitment until N 
of 126 is completed 
for efficacy analysis. 
NO = end study 
VB 
V1 
VF 
LL S 
VB 
V1 
VF 
LL S 
Security phase 
Efficacy phase 
VB= Baseline visit 
V1= Visit 1. Safety visit. 
VF= Final visit. Assessment of final outcome variables. 
Ll S= Safety call 


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1.3 Study schedule 
PROCEDURES 
VB 
D 1 
V1 
D 8 to ± 1 
VF 
D 29 to +1 
LLS 
D 35 ± 1 
FCI Signature 
X 
 
 
 
Medical record* 
X 
 
 
 
Vital signs 
X 
X 
X 
 
OSDI 
X 
 
X 
 
Evaluation of concomitant 
medications 
X 
X 
X 
 
Urine pregnancy test 
X 
 
X 
 
MAVC 
X 
X 
X 
 
Ocular surface stains 
X 
X 
X 
 
TRPL 
X 
X 
X 
 
Comprehensive 
ophthalmological evaluation 
X 
X 
X 
 
Eligibility criteria 
X 
 
 
 
PI Allocation 
X 
 
 
 
EA Assessment 
X 
X 
X 
X 
Delivery of the PI and start of 
intervention 
X 
 
 
 
Delivery of patient materials 
and instructions for 
completion (Subject Diary) 
X 
 
 
 
Subject Diary Evaluation 
 
X 
X 
 
Adherence assessment 
 
X 
X 
 
Subject continuity assessment 
 
X 
X 
 
Return of PI and subject diary 
 
 
X 
 
*Includes somatometry and general physical examination 
 
 
 


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2. Introduction and Background 
2.1 Theoretical framework 
Dry eye is currently defined as a multifactorial ocular surface disease characterized by a loss of tear 
film homeostasis accompanied by ocular symptoms, in which ocular surface instability and 
hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play 
etiological roles. [1] 
Dry eye is a common disease; the initial report of the TFOS DEWS I Epidemiology Subcommittee 
concluded that the worldwide prevalence of dry eye in individuals over 50 years of age was between 
5% and 30%.  [2]One of the main challenges facing epidemiological studies has been the lack of 
standardized definition and classification of dry eye. Despite the efforts of TFOS DEWS I and TFOS 
DEWS II to standardize these criteria, this has not yet been achieved. The TFOS DEWS II Epidemiology 
Subcommittee report indicated a prevalence of 5% to 50% in studies that included symptoms, with 
or without signs; for studies in which the diagnosis was based primarily on signs, the prevalence was 
even higher, reaching 75%. [3] 
The incidence of the disease has been reported in few studies. The Beaver Dam Eye Study 
established, in a Caucasian population aged 48–91 years, that 13.3% (95% CI 12.0–14.7%) of 
individuals developed symptomatic dry eye at 5 years and 21.6% (95% CI 19.9–23.3%) at 10 years. 
Age is a risk factor for increased incidence with an odds ratio of 1.2x (1.1–1.3) per 10-year increase. 
[4] 
Although there is no formal study on the prevalence of the disease in Latin American countries, 
various reports suggest a higher prevalence of severe symptoms and clinical diagnosis of dry eye in 
the Hispanic population compared to the Caucasian population.[5] [6] 
The current definition of TFOS DEWS II does not require the presence of any specific sign for 
diagnosis; instead, it emphasizes tear film homeostasis. The tear film plays an essential role in 
lubricating and protecting the ocular surface, as well as maintaining a smooth refractive surface for 
optimal visual performance. [7] 
Physiologically, homeostasis describes the state of equilibrium within the body with respect to its 
various functions and the chemical composition of fluids and tissues. When applied to dry eye, the 
concept recognizes the possibility of numerous changes that can occur in the tear film and ocular 
surface in response to one or more underlying causes of dry eye.  [7, 8]Altered homeostasis is 
considered the unifying characteristic that describes the fundamental process in the development 
of dry eye. 
The most current classification of dry eye attempts to eliminate any perception of exclusivity by 
indicating that the diagnoses of aqueous deficiency and evaporative dry eye exist as a continuum 
rather than as separate entities. Elements of each should be considered in diagnosis and treatment. 
[1] 


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This classification system incorporates assessment elements to clarify the diagnosis, from which 
various etiologies can be considered and appropriate treatment plans can be established. 
Appropriate treatment of ocular surface diseases (OSD) with a differential diagnosis that masks dry 
eye increases the chances of successful treatment and allows for the identification and appropriate 
management of any coexisting components of the condition attributable to dry eye. 
Figure Figure 2incorporates a clinical decision algorithm based on current knowledge of dry eye 
pathophysiology . 
 
Figure 2Dry eye classification 
Adapted from TFOS DEWS II Definition and Classification Report [1] 
Tear replacement with ocular lubricants is traditionally considered a cornerstone of dry eye 
treatment, and numerous topical formulations are available. These non-pharmacological products 
are often referred to as "artificial tears," which, as their name suggests, attempt to replace and/or 
supplement the natural tear film. However, these products do not address the underlying 
pathophysiology of dry eye, and the mechanisms of any palliative action are generally poorly 
understood. [9] 
Tear substitutes consist of various products, typically targeting one or more layers of the tear film. 
The wide variety of properties of these ocular lubricants has been described elsewhere. [10, 11, 12, 
13, 14] 
Ocular lubricants are largely considered safe, although some side effects have been reported, 
primarily blurred vision, varying levels of “ocular discomfort,” and foreign body  [15]sensation . 
Relatively few randomized controlled trials have compared the relative superiority of one product 
versus another for the treatment of dry eye.  [16]A recent Cochrane systematic review assessing the 
effect of ocular lubricants for the treatment of dry eye included 43 randomized controlled trials 
comparing various lubricant formulations with no treatment or placebo.  [15]The primary outcome 


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measure was patient-reported symptoms. The authors reported that the overall quality of the 
evidence was low for the different tear supplement formulations compared in the review and 
concluded that, although artificial tears may be effective for the treatment of dry eye, there remains 
a need for future research to allow firm conclusions to be drawn about the effectiveness of 
ophthalmic lubricant formulations. 
Dry eye management is complicated due to its multifactorial etiology. Developing the simple 
principle that "diagnosis precedes treatment" means that physicians must do their best to identify 
the degree to which OS contributes to their patients' presentation. This aspect of determining the 
main causative factors of dry eye is critical for proper management. 
Figure Figure 3a diagnosis should be made and diagnostic testing performed to determine whether 
the patient actually has dry eye and whether they generally show more signs of dry eye. Once the 
diagnosis is confirmed, the severity of the disease, along with the determination of the etiological 
subtype, will allow for the development of an appropriate treatment plan. 
 
Figure 3Diagnosis and management of dry eye 
*Fluorescein is used when TRPL-NI is unavailable. *If more than one homeostasis marker test is performed, the order 
should be: TRPL-NI, osmolarity, TRPL with fluorescein, and stains. Adapted from the TFOS DEWS II Management and 
Treatment Report 
• 
How severe is the eye discomfort? 
• 
Do you have dry mouth or inflammation of any glands? 
• 
How long have your symptoms lasted, was there any triggering factor? 
• 
Has your vision been affected, does it clear up when you blink? 
• 
Are the symptoms or redness much worse in one eye than in the other? 
• 
Have your eyes become itchy, swollen, crusty, or have they been draining? 
• 
Do you wear contact lenses? 
• 
Have you recently been diagnosed with any general illness, or are you taking any 
medication? 


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+ Detailed eye examination 
Table 1Triage questions 
Stage 1: 
• 
Education according to the disease, its management, treatment and prognosis 
• 
Modification of the local environment 
• 
Education according to dietary modifications 
• 
Identification and modification/elimination of offending topical and systemic 
medications 
• 
Eye lubricants 
• 
Eyelid hygiene and warm compresses 
Stage 2: 
If the above options are inadequate, consider the following: 
• 
Treatment for Demodex 
• 
Tear preservation 
o 
Tear duct occlusion 
o 
Wet chamber goggles 
• 
Night treatments (e.g. ointments) 
• 
Physical warm-up and meibomian gland expression 
• 
Pulsed light therapy 
• 
Prescription of: 
o 
Antibiotics or their combination with steroids on eyelid margins 
o 
Topical steroids (limited duration) 
o 
Topical secretagogues 
o 
Topical immunomodulators 
o 
Topical LFA-1 antagonists 
o 
Topical macrolides or tetracyclines 
Stage 3: 
• 
Oral secretagogues 
• 
Autologous serum 
• 
Therapeutic contact lenses 
Stage 4: 
• 
Topical steroids (extended duration) 
• 
Amniotic membrane grafts 
• 
Surgical occlusion of tear ducts 
• 
Other surgical approaches. 
Table 2Stages of dry eye treatment 
Treatment algorithms are often constructed to recommend a sequence of treatments according to 
disease stage, but this is not possible for dry eye, as it is a complex condition that varies from patient 
to patient in both severity and character. However, with the intention of assisting ophthalmic 
physicians in creating a logical, evidence-based treatment approach, the treatment algorithm shown 
in Table 2. For patients who do not respond to a given level, or who show greater severity, the next 
higher level is recommended, and in some cases, the previous treatment may be continued in 
addition to any new treatments. In general, the approach is to start with low-risk, commonly 
available conventional treatments, such as ocular lubricants for early stages of the disease, and 
progress to more advanced treatments for more severe forms. 


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2.2 Background on the product under study 
2.2.1 Pharmacology of the investigational product 
Propylene glycol is considered a demulcent or humectant in ophthalmic lubricant formulations. 
These agents are used to lubricate the ocular surface, thereby helping to reduce associated 
discomfort and irritation. 
Propylene glycol is a colorless, viscous, water-soluble polymer. Its chemical name is propane-1,2-
diol (molecular formula: C 3 H 8 O 2 ), with a molecular weight of 76.1 g/mol. [17, 18] 
The physical properties of propylene glycol in contact with the ocular surface modify tear viscosity. 
The lipid layer of the nanoemulsion acts as a surfactant, helping to spread nonpolar lipids into the 
aqueous component of the tear film. It thus provides a barrier between the two phases and provides 
a support structure for the nonpolar phase. The combination of these helps reduce tear film 
evaporation.[19] 
Due to the nature of propylene glycol, a large molecule that does not penetrate the ocular barrier, 
the pharmacokinetic profile of propylene glycol for ophthalmic administration has not been 
described. However, considering the route of elimination through the nasolacrimal duct, this 
fraction could follow the profile described for oral administration. 
2.2.2 Product efficacy under investigation 
Propylene glycol's effectiveness as a humectant is based on its ability to retain water, up to three 
times its own weight,  [20]combined with the previously mentioned characteristics conferred by its 
nanoemulsion formulation. 
There is no information yet on the efficacy of Nanodrop®; however, propylene glycol has been 
included in formulations that have been studied in clinical trials. 
2.2.3 Safety of the investigational product 
The U.S. Food and Drug Administration (FDA) has determined that propylene glycol is “generally 
regarded as safe” (GRAS) for use in food, cosmetics, and drug products. 
In addition, the FDA created a monograph in the late 1980s considering the wide variety of 
components present in ocular lubricants. The monograph determines that ophthalmic lubricants, in 
a dosage form suitable for ophthalmic application, are generally considered safe and effective if 
they contain the ingredients at the concentrations specified in the monograph. Propylene glycol is 
found in this monograph at concentrations of 0.2% to 1%. [21] 
2.2.4 Summary of the pharmaceutical development of the investigational product 
Nanodrop® was developed by Laboratorios Sophia, SA de CV. It has physicochemical 
characterization and an accelerated and long-term stability protocol. A preclinical safety and toxicity 
study was conducted in New Zealand albino rabbits, with 90-day QID application of Nanodrop®. 
Follow-up visits were conducted throughout the 90 days, with a final visit considered for outcome 
variables. Safety variables included conjunctival hyperemia, discharge, ocular surface staining, and 


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incidence of adverse events; toxicity variables were histopathological changes in the cornea and 
conjunctiva. Nanodrop® was considered safe for ophthalmic application. 
2.3 Background on the research 
2.3.1 From the research question 
There is no prior clinical trial data on Nanodrop®. However, the efficacy and tolerability of Systane® 
Balance have been previously evaluated in three single-center clinical studies.  [22, 23, 24]Systane® 
Balance is the comparator for the present study. It shares with Nanodrop® the use of 0.6% propylene 
glycol, both in ophthalmic emulsion dosage form. However, Nanodrop® is classified as a 
nanoemulsion. 
In all three clinical studies of Systane® Balance, the endpoints evaluated were TRPL, comfort, blurred 
vision, and lipid layer thickness. Systane® Balance was well tolerated, and the final results were 
consistently better than baseline. 
2.4 Risk benefit assessment 
2.4.1 Known potential risks 
Ocular lubricants are safe formulations. Propylene glycol has a known safety profile. The diagnostic 
tests considered in the study design are also considered safe. 
The only anticipated side effects with ophthalmic applications are burning, a foreign body sensation, 
and blurred vision. These are mild and transient, lasting no more than one minute post-instillation. 
2.4.2 Known potential benefits 
Potential benefits include relief of symptoms associated with dry eye and the likely restoration of 
tear film homeostasis. 
2.5 Problem statement 
Although the pathogenesis of dry eye is multiple and its semiotics variable, the different treatment 
phases have a common denominator: the use of ocular lubricants. There is a wide variety of topical 
lubricants, with different moisturizing agents; however, there is no evidence that one is better than 
another. 
While ocular lubricants have not been shown to be sufficient to completely resolve the ocular 
surface alteration and inflammation seen in patients with dry eye, they have been shown to be 
effective in providing protection to the ocular surface and reducing symptoms and clinical findings. 
Nanodrop®'s formulation of 0.6% propylene glycol in a nanoemulsion could function as an effective 
lubricant that protects the ocular surface and reconstructs the tear film, thanks to its properties. 
2.6 Justification 
Patients with dry eye, regardless of its etiology and severity, will need to use ocular lubricants to 
reduce symptoms and improve their quality of life. 


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Ocular lubricants are the first-line treatment for ocular symptoms related to dry eye in self-
reportedly healthy subjects, with a prevalence of 5% to 35% in those over 50 years of age.  [25]If we 
add to this the number of patients who report occasional symptoms or symptoms that are 
dependent on a work or occupational situation and who will use them intermittently throughout 
their lives, the population spectrum that will have access to these medications is very broad. It is 
estimated that 50% of patients diagnosed with dry eye without concomitant diseases will use more 
than two types of ophthalmic solutions in 5 years of treatment. 
Nanodrop® is an ophthalmic lubricant formulated as a nanoemulsion for which documentation of 
its safety and efficacy profile is required. It is the first emulsion lubricant in Laboratorios Sophia, SA 
de CV's ocular lubricant portfolio. 
 
 


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3. Objectives and hypotheses 
3.1 Primary objectives 
3.1.1 Primary security objective 
To evaluate the safety of ophthalmic application of Nanodrop® by quantifying the incidence of 
unexpected Adverse Events (AEs). 
3.1.2 Primary efficacy objective 
To demonstrate the non-inferiority of Nanodrop® compared to Systane® Balance in the treatment 
efficacy of patients with dry eye, using the OSDI (Ocular Surface Disease Index) test score. 
3.2 Secondary objectives 
3.2.1 Secondary security objective 
To compare the safety of ophthalmic application of Nanodrop® versus Systane® Balance by 
quantifying the incidence of expected adverse events. 
3.2.2 Secondary efficacy objectives 
To compare the efficacy of ophthalmic application of Nanodrop® versus Systane® Balance through 
changes in BCVA. 
To compare the efficacy of ophthalmic application of Nanodrop® versus Systane® Balance by 
changes in conjunctival staining with lissamine green. 
To compare the efficacy of ophthalmic application of Nanodrop® versus Systane® Balance using 
changes in corneal fluorescein staining. 
To compare the efficacy of ophthalmic application of Nanodrop® versus Systane® Balance by means 
of changes in TRPL. 
3.3 Exploratory objectives 
Compare the average daily applications of Nanodrop® versus Systane® Balance. 
3.4 Hypothesis 
3.4.1 Security hypothesis 
H 0 =Nanodrop® is safe in its ophthalmic application, presenting an incidence of unexpected AEs, 
related to the PI less than 20% of the population of the Nanodrop® safety group 
H 1 = Nanodrop® is not safe for ophthalmic application, as it presents an incidence of unexpected 
AEs related to the PI greater than 20% of the population in the Nanodrop® safety group. 


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3.4.2 Efficacy hypothesis 
H 0 = Nanodrop® is inferior to Systane® Balance by more than 5 points on the OSDI test score 
H 0 : µ A - µ B > δ 
H 1 = Nanodrop® is inferior to Systane® Balance by 5 points or less on the OSDI test score 
H 1 : µ A - µ B ≤ δ 
 
 


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4. Study design 
4.1 Design Overview 
Phase I-II, comparative, non-inferiority, active-controlled, parallel-group, double-blind, randomized 
clinical trial. Safety analysis is performed upon completion of the first 12 subjects in the Nanodrop® 
group. If fewer than 20% of unexpected AEs related to the investigational product occur, 
recruitment continues until the sample size for efficacy analysis is complete. (See pp. 14) 
4.2 Justification of the study design 
Propylene glycol, a component of Nanodrop®, is a compound classified by the FDA as GRAS for use 
in food, cosmetics, and drug products. The propylene glycol concentration falls within the 
specifications of the FDA monograph for ophthalmic lubricants considered safe. 
Because of this, the design of a separate Phase I study is not considered necessary; the advantages 
of the proposed design include having data on the efficacy variables from all subjects included in 
the study for the efficacy analysis. The safety phase will allow for the identification of unforeseen 
risks related to the study's formulation or procedures without interfering with the efficacy analyses. 
4.3 Expected duration 
The total duration of the study, from the first patient visit to the final report, is estimated to be 11 
months. 
The planned recruitment period is 9 months. Considering the proposed sample size of 126 subjects, 
the average recruitment rate throughout the study should be no less than 0.5 subjects per day. 
The approximate duration of each subject in the study is 35 days. 
 
 


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5. Study population 
5.1 Eligibility criteria 
5.1.1 Inclusion criteria 
− 
Have the ability to voluntarily grant signed informed consent. 
− 
Be able and willing to comply with scheduled visits, treatment plan, and other study 
procedures. 
− 
Be willing to modify your lifestyle activities. See 5.3 Lifestyle considerations. 
− 
Be of age. 
− 
Women of childbearing potential must ensure continued use (started ≥ 30 days prior to 
signing the FCI) of a hormonal contraceptive method or IUD during the study period. 
− 
Present diagnosis of dry eye, defined by: 
o OSDI ≥ 13 points 
o + 1 of the following: 
▪ 
Corneal staining with more than 5 sites 
▪ 
Conjunctival staining with more than 9 sites 
▪ 
Tear film break-up time < 10 seconds 
5.1.2 Exclusion criteria 
− 
For women: be pregnant, breastfeeding, or planning to become pregnant during the study 
period. 
− 
Having participated in another clinical research study ≤ 30 days prior to the screening visit. 
− 
Having previously participated in this study. 
− 
Present a BCVA of 20/200 or worse in either eye. 
− 
Present an additional ophthalmological diagnosis of: 
o Allergic, viral or bacterial conjunctivitis. 
o Anterior blepharitis. 
o Demodex. 
o Parasitic eye infections. 
o Unresolved ocular trauma. 
o Healing diseases of the ocular surface. 
o Corneal or conjunctival ulcers. 
o Filamentous keratitis. 
o Neurotrophic keratitis. 
o Bullous keratopathy. 
o Neoplastic diseases of the ocular surface or annexes. 
o Diseases with fibrovascular proliferations on the conjunctival and/or corneal 
surface. 
o Diseases of the retina and/or posterior segment that require treatment or threaten 
the visual prognosis. 
o Glaucoma. 
− 
Have dry eye management that requires implementation of Stage 2 treatments in the DEWS 
II Staged Treatment and Management for Dry Eye Disease recommendations. See Table 2. 


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− 
Have a history of drug addiction or dependence, currently or within the last two years prior 
to signing the FCI. 
− 
Have a history of ocular surgical procedures within the last 3 months prior to signing the 
FCI. 
− 
Wear soft or hard contact lenses. You may be admitted if you can discontinue use of contact 
lenses during the study. You must not wear contact lenses for 15 days prior to enrollment. 
− 
Having another medical condition, acute or chronic, that, in the opinion of the investigator, 
could increase the risk associated with participation in the study or the administration of 
the investigational product, or that could interfere with the interpretation of the study 
results. 
− 
Have a known hypersensitivity to the components of the investigational products. 
− 
Be or have an immediate family member (e.g., spouse, parent/legal guardian, sibling, or 
child) who is an employee of the research site or the sponsor and who is directly involved 
in this study. 
5.2 Criteria for eliminating and replacing subjects 
5.2.1 Elimination criteria 
− 
Withdrawal of the FCI letter. 
− 
Presentation of a serious adverse event, whether or not related to the investigational 
product, which, in the opinion of the PI and/or the sponsor, could affect the patient's ability 
to safely continue study procedures. 
− 
Non-tolerability or hypersensitivity to any of the compounds used during the tests 
(fluorescein, lissamine green, tetracaine). 
− 
Non-tolerability or hypersensitivity to any of the investigational drugs. 
5.3.1 Substitution of subjects 
The sponsor, with prior authorization from the research ethics committees, may decide to replace 
subjects who withdraw their FCI or those who are lost to follow-up, if it is necessary to balance the 
study groups so that they are evaluable, or to complete the minimum population to be evaluated 
for the efficacy analysis. 
The results obtained from the replaced subjects will continue to be used for safety analysis. 
5.3 Lifestyle considerations 
For the study, participants may need to modify some lifestyle activities to accomplish the 
following: 
- 
Refrain from smoking. 
- 
Refrain from using electronic vaporizers. 
- 
Avoid immersing yourself in water without eye protection ( goggles ). 
- 
Avoid direct exposure to fans (including air conditioning vents) during activities that involve 
vision. 24 hours before your checkup visits. 
- 
Maintain your sleep-wake cycle with the one you entered the study. 


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5.4 Scrutiny failures 
A screening failure is defined as a participant who agrees to participate in the study, giving their 
consent, but who is not assigned to a treatment group; that is, they do not enter the study. The 
following information regarding screening failures must be reported, at a minimum: 
- 
Demographic data. 
- 
Details of the counting failure (specify whether due to eligibility criteria, which one, or some 
other reason for the failure). 
- 
Presence of serious adverse events during the scrutiny. 
This is necessary to comply with the CONSORT ( Consolidated Standards of Reporting Trials ) 
guidelines for publishing results or to respond to potential questions from regulatory authorities. 
Subjects who do not meet the eligibility criteria for participation in the study due to a specific 
modifiable factor may be re-screened. Subjects in this situation must use the same initial screening 
number. 
5.5 Recruitment and retention strategies 
This is a Phase I-II study planned for six centers. The selected centers will be responsible for subject 
recruitment. Recruitment will be competitive, with a proposed initial recruitment of 21 subjects per 
center; however, this will be contingent on the performance of each center, so this number may 
vary by center. 
The minimum expected recruitment rate per center is 0.2 subjects per day. 
Subject participation in the study is approximately 35 days, during which time they are only required 
to attend two visits after the baseline visit, so retention issues are not anticipated. However, 
subjects will be eligible for travel and travel expenses to attend their visits. Other strategies to 
improve subject retention include, but are not limited to: 
▪ 
Clearly communicate the importance of the study and the benefits the population will gain 
from its results. 
▪ 
Make calls or send text messages to remind yourself of appointments or activities to do. 
▪ 
Provide a printed calendar and ID card to remind you of upcoming appointments and 
activities, as well as their estimated duration. 
▪ 
Offer flexible business hours. 
▪ 
Systematic organization of the study procedures, so that the subject does not stay longer 
than necessary during his visit. 
▪ 
Minimize subject wait times. 
All materials to be delivered to the subject or recruitment strategies implemented by the Centers 
will be submitted for approval by the corresponding committees. 
5.6 Procedure in case of loss of follow-up 
For this protocol, loss to follow-up is defined as those subjects who were randomized, who at some 
point were active subjects in the study, but their final evaluation could not be completed. 


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If the participating subject does not attend their appointment, the research site will call to 
determine the reason and attempt to schedule a new appointment within the established window 
or an unscheduled appointment. If an appointment cannot be scheduled, the subject will be asked 
about the presence of adverse events and the reason for discontinuing the study, as minimum 
information. 
A loss to follow-up <5% is not considered to represent a problem for the validity of the results 
obtained. [26, 27]  
5.7 Subject identification 
Study subjects will be identified by a number and the initials of their name. 
The initials of the subject of study will be obtained starting with the first letter of the name, followed 
by the first letter of the first surname and the first letter of the second surname, obtaining a 
maximum of three letters. In case the person has two names or a compound surname, the first letter 
will always be used. 
Example: 
A. A rieh Daniel M ercado C arrizalez  
 
B. J uan D e la Torre O rozco 
a. Initials: AMC   
 
 
 
b. Initials: JDO 
During the screening phase, participants will be assigned a consecutive three-digit number. Once 
the subject has been selected, they will be assigned a number that will identify them throughout 
the study. This code will consist of eight numbers in the following order, from left to right: 
• 
three digits of the molecule under study according to the name given by the sponsor. 
• 
two digits corresponding to the research center number. 
• 
three digits of the consecutive number assigned to its inclusion in the research center. 
Example: 
 
 
 
 
176-01-001 
Key to the 
molecule 
Inclusion number 
Center number 


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6. Investigational product 
6.1 Managed Products 
6.1.1 Investigational product 
− 
Generic name: Propylene glycol 
− 
Distinguishing name: Nanodrop® (PRO-176) 
− 
Active ingredients: Propylene glycol 0.6%. 
− 
Pharmaceutical form: Ophthalmic emulsion 
− 
Presentation: multi-dose dropper bottle, 10 ml. 
− 
Prepared by: Laboratorios Sophia, SA de CV 
− 
Solution description: Homogeneous emulsion, free of visible particles. 
− 
Packaging description: White bottle with a capacity of 10 mL, made of low-density 
polyethylene. 
6.1.2 Reference product 
− 
Generic name: Propylene glycol 
− 
Distinguishing name: Systane® Balance 
− 
Active ingredients: Propylene glycol 0.6% 
− 
Pharmaceutical form: Ophthalmic emulsion 
− 
Presentation: multi-dose dropper bottle, 10 ml. 
− 
Manufactured by: Alcon Laboratories, Inc. 
6.1.2.1 Justification of the reference product 
Systane® Balance is a commercially available lubricant with a previously described safety and 
efficacy profile. It is a propylene glycol ophthalmic emulsion at the same concentration as 
Nanodrop®. Furthermore, it will be a direct commercial competitor. 
6.1.3 Dosage of investigational products  
The minimum dosage to follow is 1 drop, four times a day, in both eyes. 
However, subjects may increase the number of applications, if they deem necessary, as many 
times per day as they deem necessary. Each application must be recorded in the "Subject Diary." 
6.1.3.1 Justification of the dose 
Ophthalmic lubricants are generally prescribed as needed (pro re nata [PRN]).  [28]However, the 
study by Asbell et al. compared the efficacy of QID versus PRN dosing. Their results showed that, 
although there was no difference in clinical signs, the QID group had greater symptom 
improvement.  [29]For this reason, the minimum dosage proposed for this study, and as the basis 
for calculating adherence, is 1 drop four times daily. However, the possibility of increasing this PRN 
dosage remains open to assess whether more applications are better for the patient. 


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6.2 Storage and handling of research products at the study center 
Delivery will be made via a courier service contracted by the sponsor, specifically selected for this 
purpose, to the address of the research center in accordance with the study plan. 
Reception will be carried out by the assigned research team staff. They must verify the condition of 
the primary packaging (box). If it shows alterations or defects in its integrity that, in their judgment, 
could have damaged the contents, they must report this to the sponsor. If the package shows no 
significant defects, they will proceed to open it. 
Inside, you should locate the receipt acknowledgment document and the temperature data logger 
. You should check that the recorded temperature meets the specifications for its transport and 
storage. You will verify the contents (PI) with what is reported on the document. If the document 
matches the contents, you will sign the receipt and send it to the sponsor. If not, you will notify the 
sponsor. 
Storage and safeguarding are the responsibility of the research center. The medication must be kept 
in a secure area with restricted access. 
Storage temperature should be 2°C to 30°C. 
The research center is required to record the temperature recorded in the data logger , using the 
designated format, every day while the protocol is in effect and has PIs. These data will be reviewed 
by the clinical monitor according to the data logger records. 
In the event of material loss, this must be documented in the input and output log along with a clear 
description of the mechanism by which the loss occurred. 
Upon completion of the protocol, all study materials will be retrieved by the sponsor as part of the 
closure audit. The final return of materials will be made by the principal investigator or the person 
designated by the principal investigator to return materials at the end of the study. 
The sponsor reserves the right to initiate civil and criminal action against the principal investigator 
in the event of undocumented material missing at the end of the study. 
6.3 Concomitant treatments and medications not authorized during the study 
Subjects successfully enrolled in the study and who meet the eligibility criteria may continue 
systemic treatment for their underlying conditions. If they require the introduction of a new 
approved medication during the course of the study, they may do so. All concomitant medications 
used must be duly reported in the clinical record notes and in the corresponding section. 
Permitted medications: 
- 
Ophthalmic: 
All permitted medications administered ophthally during the study must wait a minimum of 10 
minutes after the last application of the study or reference treatments. This is to avoid treatment 
interactions with the tear film, based on the tear flow rate and physiological tear volume. [30]  
o Tetracaine 0.5% 
o Tropicamide 0.8% / Phenylephrine 5% 


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o All topical antibiotics except tetracyclines 
- 
Administered by a route other than ophthalmic: 
o Any medication whose effect may be susceptible to modifying any of the efficacy, 
safety or tolerability parameters of this research protocol must be notified to the 
clinical monitor or the sponsor's scientific committee to determine the 
appropriateness of the participant's admission, continuation or elimination as 
appropriate. 
o Women who enter using hormonal contraceptives must continue using them 
throughout the study. 
Prohibited medications: 
- 
Any medication with ophthalmic application that is not on the list of permitted medications 
- 
Systemic steroids 
- 
Immunomodulators 
- 
Tetracyclines 
6.4 Procedure for monitoring and measuring adherence 
For more than four decades, numerous studies have been conducted on the appropriate way to 
measure and quantify medication adherence, but none have reached a consensus that could serve 
as the gold standard, both in cross-sectional and longitudinal studies. [31, 32, 33, 34, 35, 36, 37, 38] 
There are different procedures for measuring adherence to pharmacological interventions. The 
most common procedure involves self-reports, which include patient interviews, questionnaires, 
and self-monitoring diaries. Their strengths are speed, flexibility, low cost, and ease of 
implementation; they have a high degree of specificity for nonadherence, but their sensitivity and 
reliability for adherence are low. [38, 39] 
Biochemical measurement of the drug, or its metabolite, is one of the methods that best confirms 
drug use. However, in addition to being costly and impractical, it is of little use in ophthalmic 
applications, as peripheral concentrations may be undetectable; and samples from other tissues 
require more invasive methods that would be inadvisable. [38] 
Medication counting is another way to measure adherence. Classically referred to as "pill counting," 
in ophthalmology it is translated as the weight of the bottle. This is a simple, inexpensive, and 
noninvasive method. The main disadvantages of this method are: 1. It cannot confirm medication 
application (it could have been intentionally dropped or instilled outside the eye), and 2. It depends 
on the subject bringing the medication back. [38, 39] 
A multi-method approach to adherence measurement is recommended. Because there is no ideal 
adherence measure, it is appropriate to use more than one method when aiming to achieve results 
that resemble reality. Selecting two or more methods allows for balancing their strengths and 
weaknesses, thus more accurately capturing adherence levels. [37] 
Adhesion assessment will be based on the bottle's weight and will be performed taking into account 
the following information: drop weight, initial container weight, final container weight, and the total 
number of applications. The following simplified formula will be used: 


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𝐴𝑑= (𝑃𝑖−𝑃𝑓)100
𝑃𝑇
 
Where: 
Ad = adhesion 
𝑃𝑖= weight of the container delivered to the subject at the beginning 
𝑃𝑓= weight of the container returned by the subject 
𝑃𝑇 = weight of the dosage indicated for the investigational products 
𝑃𝑇= (𝑃𝑔)𝐺 
Where: 
𝑃𝑔= weight of a drop of the intervention, determined by the research and development department 
G = number of applications indicated for the investigational products 
Packaging that does not maintain its physical integrity will not be considered for the calculation of 
adhesion. 
In cases where the container is not returned, or has not maintained its physical integrity, adherence 
will be measured using the subject's diary, as follows: 
𝐴𝑑= (𝐴𝑟)100/𝐴𝑖 
Ad = Adhesion 
A r = Registered applications 
A i = Applications indicated for investigational products 
The "indicated applications for investigational products" will correspond to a minimum dosage of 4 
drops per day in each eye, i.e., 8 drops per day for 28 days (224). Because dosage increases are 
permitted, adherence rates greater than 100% may be observed. 
The research center will designate a person responsible for monitoring adherence through a diary 
during visits. Measuring adherence through weight will be the sponsor's responsibility. 
There is no standardized parameter for defining adequate adherence; it must be defined and 
outlined by the objectives of the particular research. [38]  
For this study, a minimum adherence of 70% will be considered necessary to meet the research 
objectives. Therefore, subjects with less than 70% adherence will not be considered for the efficacy 
analysis; they will only be included in the safety analysis. 
6.5 Strategies to improve adherence 
1. The PI will sensitize the subject to the importance of correctly applying the PI to achieve 
the study objectives. 
2. Direct questioning by the IP regarding the application of the PI. 
3. Delivery of a printed calendar specifying the date of the visit and its activities. 
4. Training in completing and reviewing the “Subject Diary.” 
5. If deemed necessary, text messages may be sent as reminders. The content of these 
messages must be approved in advance by the IEC. 


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7. Methods and procedures of the 
study 
7.1 From the research center 
This study will be conducted at research centers previously evaluated by the sponsor. These centers 
will be institutions or establishments that conduct health research and comply with current 
regulations. 
The research center will be responsible for forming a multidisciplinary research team to execute the 
clinical study according to the protocol. It is its prerogative to design the organization and select the 
personnel who will perform these functions. However, the sponsor requires that the Principal 
Investigator (PI) be a physician specialized in ophthalmology. 
Any person assigned responsibility for part of the study monitoring (coinvestigator, sub-investigator, 
nurse, etc.) or a specific role in the study (pharmacist, administrative assistant, study coordinator, 
etc.) must be listed in the "Delegation of Responsibilities." 
The competency and training of all individuals directly involved in study activities must be verified 
prior to the conduct of any protocol-related activities. This must be recorded, and documents 
constituting evidence of this competency and/or training must be retained in the study master file. 
The competency and training of personnel involved in the study, both at the central level and at the 
study sites, is the responsibility of the sponsor. 
The sponsor must ensure that all study center personnel participating in the study are adequately 
trained in the study (research protocol, investigator's manual, amendments, standard operating 
procedures, etc.) and in ICH Good Clinical Practices prior to the start of their participation in the 
study. Training must be documented in writing and filed in the study's master file. 
7.2 Clinical study registration 
This clinical study will be registered by the sponsor in public clinical trial registries prior to its 
initiation (enrollment of the first patient): the National Registry of Clinical Trials (RNEC) of the 
Federal Commission for the Protection against Sanitary Risks (COFEPRIS) and on a WHO primary 
registry platform. WHO primary registries meet specific criteria regarding content, quality and 
validity, accessibility, unique identification, technical capacity, and administration. WHO primary 
registries meet the requirements of the International Committee of Medical Journal Editors (ICMJE). 
7.3 Randomization and blinding 
Subject randomization will be performed using a computerized allocation system. After signing the 
FCI, the patient will receive a patient number, which will be used to pseudonymize all information 
during collection and completely anonymize it during analysis. 


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The generation will be carried out by a third party authorized by Laboratorios Sophia, SA de CV, 
through its electronic system. The information corresponding to this third party will be found in the 
file. 
Blinding will be performed by the subject, PI, and subinvestigator. Furthermore, the statistical 
analysis will be performed blinded for the final analysis. Blinding cannot be guaranteed for the 
subject. 
Masking will be done through primary and secondary packaging. 
They will be identified by identical labels. These, in compliance with current and applicable 
regulations, must contain at least: 
- 
Name, address and telephone number of the sponsor. 
- 
Pharmaceutical form and route of administration. 
- 
Batch number. 
- 
Legend “Exclusively for clinical studies” 
- 
Expiration date. 
7.3.1 Opening of the cecum 
The cecum may be opened in the following cases: 
1. Presence of a serious adverse event. 
2. Safety alert for the use of the drugs under study. 
3. In the event that the sponsor determines it for any security reason or other reason that it 
deems appropriate. 
4. In the event that the regulatory authority or the ethics committee justifiably requests it and 
deems it necessary 
7.4 Outcome variables 
7.4.1 Primary outcome variables 
- 
OSDI Test Score (TE: Day 29) 
- 
Incidence of unexpected AEs related to the PI (TE: day 8 and 29) 
7.4.2 Secondary outcome variables 
- 
Changes in BCVA (TE: day 8 and 29) 
- 
Changes in TRPL with fluorescein (TE: day 8 and 29) 
- 
Corneal fluorescein staining changes (TE: day 8 and 29) 
- 
Conjunctival staining changes with lissamine green (TE: day 8 and 29) 
- 
Incidence of expected AEs (TE day 8 and 29) 
7.4.3 Exploratory outcome variable 
- 
Average number of applications performed daily 


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7.4.4 Definition of variables, methods and scales to be used for measurement 
Variable 
Guy 
Unit (symbol) 
Measurement 
method 
Normal 
value 
Evaluation 
time 
Statistical 
test 
Primary outcome 
OSDI 
Discreet 
Points (-) 
Questionnaire 
< 13 
VB and VF 
Mann-
Whitney U 
Unexpected 
EAs related 
to PI 
Discreet 
Number of 
cases (n) 
Counting 
0 
VB, V1 and 
VF 
Mann-
Whitney U 
Unexpected 
AEs related 
to the PI 
(bis) 
Nominal 
categorical 
Present/absent 
(-) 
Observation 
Absent 
VB, V1 and 
VF 
χ 2 or 
Fisher's 
exact test 
Of secondary outcome 
MAVC 
Discreet 
Fraction (-) 
Snellen chart 
1 
VB, V1 and 
VF 
Mann-
Whitney U 
TRPL with 
fluorescein 
Continue 
Seconds (s) 
Direct 
observation 
with slit lamp 
and blue filter 
>10s 
VB, V1 and 
VF 
Mann-
Whitney U 
Corneal 
staining with 
fluorescein 
Ordinal 
Degrees (-) 
Direct 
observation 
with a slit lamp 
on the Oxford 
scale 
0 
VB, V1 and 
VF 
χ 2 or 
Fisher's 
exact test 
Conjunctival 
staining with 
lissamine 
green 
Ordinal 
Degrees (-) 
Direct 
observation 
with slit lamp 
and cobalt blue 
filter, Oxford 
scale 
graduation 
0 
VB, V1 and 
VF 
χ 2 or 
Fisher's 
exact test 
EA 
Discreet 
Number of 
cases (n) 
Counting 
0 
VB, V1 and 
VF 
Mann-
Whitne U 
EA (repeat) 
Nominal 
categorical 
Present/absent 
(-) 
Observation 
Absent 
VB, V1 and 
VF 
χ 2 or 
Fishe's 
exact 
Exploratory 
Number of 
applications 
made daily 
Discreet 
Number of 
applications 
(n) 
Count by 
Subject's 
Diary 
>4 
V1 and VF 
Mann-
Whitne U 
Table 2Operational definition of variables 
The variables, method, and scales for their measurement are described in detail below. They are 
listed in order according to Table 2 
7.4.4.1 OSDI Score 
The OSDI is a validated and reliable instrument for measuring dry eye severity. It has the 
psychometric properties necessary for use as an outcome variable in clinical studies.  [40]It consists 
of a 3-question, 12-item questionnaire. Responses are based on frequency and offer 5 options, 
ranging from 4 (all the time) to 0 (none of the time). Questions 2 and 3 also contain the option NA. 
(See 15.1.) The OSDI score is calculated based on the following formula: 


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𝑂𝑆𝐷𝐼= 𝐷 x 25
𝐸
 
Where: 
D = sum of the points of the questions answered 
E = number of items answered, those answered with NA are not counted as answered 
The OSDI score will be recorded on the Electronic Case Report Form (FERC) 
Management as an AE: An increase of more than 40% from the baseline OSDI score should be 
reported and managed as an AE due to lack of efficacy. 
7.4.4.2 Adverse events 
As defined in section 8.2, an EA It is any unfavorable medical occurrence in a subject to whom a PI 
is administered, regardless of the causal attribution. 
The management of AEs will be carried out as described in the Adverse Events section. 
The IP will record any AEs that the study subjects may present in the corresponding section of the 
FERC and will also include them in the clinical record. 
For an adequate evaluation of AEs, in addition to the targeted questioning, a Comprehensive 
Ophthalmologic Evaluation must be performed at each visit. This evaluation consists of an 
ophthalmologic examination of the eyelids and adnexa, anterior segments, and posterior segments, 
which are performed during a routine ophthalmologic examination and are not specifically included 
in the study variables. The posterior pole evaluation may be performed with direct or indirect 
ophthalmoscopy, with or without pharmacological mydriasis, at the discretion of the PI. The fundus 
will be assessed for abnormalities that could alter the study results. IOP will be measured during this 
evaluation, using the PI's chosen instrument, and should be measured after the stain evaluation. 
The results of the evaluation will be recorded in the clinical record. Only findings that the PI 
considers to be AEs will be reported in the FERC. 
The expected adverse effects associated with the use of PIs are: blurred vision, burning, eye 
irritation, foreign body sensation, and sticky eyelashes. They are expected to be transient, lasting 
no more than 30 seconds after PI instillation, and to be mild in intensity. 
7.4.4.3 Best Corrected Visual Acuity 
Visual acuity (VA) is a test of visual function. Spatial VA is the ability to distinguish separate elements 
of an object and identify them as a whole. It is quantified as the minimum angle of separation 
(located at the nodal point of the eye) between two objects that allows them to be perceived as 
separate objects. 
Snellen notation is described as the distance at which the test is performed divided by the distance 
at which the letter vertically equals 5 minutes of arc. Thus, at 6 meters, a letter 6/6 (20/20) equals 
5 minutes of arc, a letter 6/12 (20/40) equals 10 minutes, and a letter 6/60 (20/200) equals 50 
minutes. The Snellen fraction can also be expressed as a decimal (i.e., 20/20 = 1 and 20/40 = 0.5). 
[41]  


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VA will be assessed at baseline, without refractive correction, using the Snellen chart. This chart will 
be placed in a location with adequate natural or artificial lighting and at a distance of 3 m from the 
subject being assessed. Visual acuity will be measured in each eye, starting with the right eye (RE), 
asking the subject to keep both eyes open and using an occluder to cover the left eye (LE); the 
subject will read aloud the lines indicated by the evaluator. The evaluator will record the smallest 
line of letters visible as the RE VA in the clinical record. The LE is then assessed using the same 
method. 
The subject's objective and subjective refractive correction will then be performed. The subjective 
refraction result will be reported as BCVA, recorded as a fraction in the clinical record and on the 
FERC, and recorded as a decimal on the FERC. By definition, BCVA cannot be less than VA. 
Management as AE: A decrease of more than 2 lines on the Snellen chart should be reported and 
managed as an AE. 
7.4.4.4 Tear film breakup time 
One of the first aspects of the tear film to change when there is a change in the ocular surface is its 
stability. In general, if the corneal or conjunctival surface is damaged, it is unlikely that a stable 
tear film can be maintained. 
The most common method for assessing tear film stability is fluorescein-based TRPL. Once 
fluorescein has been instilled (see 7.4.4.5), the patient is asked to hold their breath after blinking 1 
to 2 times using the cobalt blue filter. The fluorescein-stained precorneal layer will shift to less 
fluorescent or nonfluorescent regions. The time elapsed from the last blink to the appearance of 
these regions is the TRPL. It is reported in seconds in the clinical record and on the FERC. 
Management as an AE: A decrease in TRPL of more than 40% from baseline should be reported and 
managed as an AE due to lack of efficacy. 
7.4.4.5 Corneal staining with fluorescein 
A drop of topical anesthetic is instilled into the conjunctival fornix. A second drop is then applied to 
the tip of the fluorescein strip, allowing it to sit on the strip for 5 seconds to elute the dye, shaking 
off the excess at the end. A small amount of contact is made between the strip and the conjunctiva 
in the temporal fornix while the patient looks upward, avoiding damaging the conjunctiva. After 
assessing the TRPL, 4 to 8 minutes after instillation of the dye, the corneal fluorescein staining is 
assessed using a slit lamp with a cobalt blue filter. It is graded according to the Sjögren's Clinical 
Collaboration Alliance (SICCA) Ocular Staining Grading (OSG). [42]  
According to the CTO, grade 0 corresponds to the absence of punctate epithelial erosions (PEEs); 
grade 1 is defined as the presence of 1-5 PEEs; grade 2 corresponds to 6-30 PEEs; and >30 PEEs will 
be classified as grade 3. An additional grading point will be added if: 1) PEEs with a diameter of 4 
mm are present in the central portion of the cornea; 2) filaments are observed; and 3) confluent 
staining patches, including linear staining, are observed.  [42]See Figure 4 
The IP will record in the file and with the FERC the grades awarded for corneal staining of OD and 
OS, respectively. The maximum grade per eye is 6. 


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Management as AE: Corneal staining that is greater than that recorded as baseline will be 
considered AE due to lack of efficacy. 
7.4.4.6 Conjunctival staining with lissamine green 
After the fluorescein examination, a drop of saline solution will be applied to the tip of the lissamine 
green strip, allowing it to sit on the strip for 5 seconds to elute the dye. A drop from the strip is 
instilled into the temporal fornix while the patient looks up, without damaging the conjunctiva. The 
patient may be asked to blink repeatedly to avoid accumulation in the conjunctival folds. The 
examination should be performed between 1 and 4 minutes after instillation through a neutral 
density filter or a red-free filter. It will be graded according to the SICCA CTO. [42] 
In CTO, grade 0 is defined as the presence of 0 to 9 lissamine green staining points in the 
interpalpebral bulbar conjunctiva (scoring the temporal and nasal portions separately); grade 1 is 
defined by the presence of 10 to 32 points; grade 2 by 33 to 100; and grade 3 by >100 points. 
Because of the difficulty in counting individual points in a moving eye, any area ≥4 mm 2 of confluent 
points is considered >100 points  [42]. See Figure 4 
The IP will record, in the file and with the FERC, the sum of the grades awarded to the temporal and 
nasal portions for OD and OS, respectively. The maximum grade per eye is 6. 
Management as AE: Conjunctival stains that obtain scores ≥ 3 and that are higher than the baseline 
score will be considered AE due to lack of efficacy. For example: Subject X obtains a baseline score 
of 1, and at a follow-up visit, his staining is rated as 2. This does not need to be managed as AE. If he 
obtains a score of 3 or higher, he should be managed as AE. 
7.4.4.7 Number of applications made daily 
According to the PI dosing schedule, subjects may increase the number of daily instillations. They 
should not decrease the number to four per eye per day. 
An instillation is considered separate when there are more than 10 minutes between each 
instillation. Similarly, if two or more drops are applied to a single eye during a single instillation, it 
will be considered one instillation. The subject must record each instillation performed during the 
day in the Subject Diary. The PI will tally the number of applications recorded in the diary and divide 
it by the number of days of treatment. This average will be recorded in the FERC. 
 
 


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Figure 4SICCA Ocular Staining Rating 
Modified from Whitcher et al. [42] 
 
7.5 Program of visits and activities of the study 
7.5.1 Description of activities per visit 
The procedures are listed in the order in which they are suggested to be performed, trying to 
maintain the consistency of the evaluations and, as far as possible, from the least invasive to the 
most invasive. 
7.5.1.1 Baseline Visit 
▪ 
Signature of the ICF : refers to the signing of the written informed consent document. 
Without informed consent, none of the study procedures can be performed. 
▪ 
Medical record: refers to the technical, clinical, and legal document that chronologically 
records the patient's health conditions, medical procedures, and other procedures 
performed on the patient. It includes anthropometric measurements, anamnesis, and a 
comprehensive ophthalmologic examination that allows determining the patient's 
eligibility, i.e., evaluation of both eyes and ocular adnexa, slit-lamp examination of the 
ocular surface and anterior segment, and fundoscopy. If the patient is taken from the study 
Lissamine green 
(conjunctiva 
Fluorescein 
(cornea only) 
Grade  Points 
Grade  Points 
0 
0-9 
1 
10-32 
2 
33-100 
3 
>100 
0 
0 
1 
1-5 
2 
6-30 
3 
>30 
Score by staining pattern: 
Additional points for fluorescein 
staining only: 
+1 if there are patches of confluent 
staining 
+1 if there is staining in the pupillary 
area 
+1 if there are filaments 


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center's established population base, the existing medical record may be used; only one 
update is required . 
▪ 
Vital signs: This refers to heart rate, respiratory rate, blood pressure, and temperature. This 
information should be recorded in the patient's medical history and progress notes. 
▪ 
OSDI Score: See 7.4.4.1 
▪ 
Evaluation of concomitant medications: refers to the IP questioning the subject, inquiring 
about the use of medications. 
▪ 
Urine pregnancy test: This refers to the performance of a rapid pregnancy test in all women 
of childbearing age who wish to enter the study. By childbearing age, we mean women who 
have experienced menarche but have not yet experienced menopause. Menopause is 
defined as 12 months since the last menstrual period in women over 40 years of age, or 
those who have undergone a hysterectomy or bilateral oophorectomy. Women of 
childbearing age using contraceptive methods, including bilateral tubal obstruction, must 
undergo a pregnancy test. This test will be performed by the PI or a designated team 
member according to the instructions on the device provided by the sponsor. 
▪ 
MAVC: Ver 7.4.4.3 
▪ 
TRPL: See 7.4.4.4 
▪ 
Ocular surface stains: See 7.4.4.5and 7.4.4.6 
▪ 
Ophthalmological evaluation: See 7.4.4.2 
▪ 
Eligibility criteria: Refers to the PI's review, which verifies that the subject can be included 
in the study if they meet the inclusion criteria and do not meet the exclusion criteria. See 
5.1 
▪ 
PI Allocation: This refers to determining the intervention the patient will follow during the 
study. This assignment will be carried out according to section 7.3. This assignment will be 
made at the baseline visit (day 1). 
▪ 
Delivery of the PI and start of intervention: Refers to the delivery of the PI to the study 
patient by the research center. See 
▪ 
EA Assessment: See 7.4.4.2 
▪ 
Delivery of patient materials and instructions for completion: Refers to the IP providing the 
subject with the patient diary, identification card, and adherence-enhancing calendar. The 
assigned staff will provide the subject with pre-training on how to complete the diary. 
7.5.1.2 Visit 1 
▪ 
Vital signs: See above 
▪ 
Evaluation of concomitant medications: See above 
▪ 
MAVC: Ver 7.4.4.3 
▪ 
TRPL: See 7.4.4.4 
▪ 
Ocular surface stains: See 7.4.4.5and 7.4.4.6 
▪ 
Ophthalmological evaluation: See 7.4.4.2 
▪ 
EA Assessment: See 7.4.4.2 
▪ 
Subject Diary Assessment: This refers to the review of the Subject Diary instrument by the 
PI or designated facility staff; it will be reviewed for correct completion, as well as the 
patient's comments. The PI may question these comments for AEs. At the PI's discretion, 
the comments may or may not be reported as AEs. 


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▪ 
Adherence assessment: Adherence will be calculated by recording applications in the 
subject's diary. Adherence will be calculated based on a dosage of 4 applications per day. 
In addition, the average number of daily applications will be recorded according to section 
7.4.4.7 
▪ 
Subject Continuance Assessment: Refers to the PI's determination of the subject's desire 
to continue participating in the study. 
7.5.1.3 Final Visit 
▪ 
Vital signs: See above 
▪ 
OSDI Score: See 7.4.4.1 
▪ 
Evaluation of concomitant medications: See above7.5.1.1 
▪ 
Urine pregnancy test: See above7.5.1.1 
▪ 
MAVC: Ver 7.4.4.3 
▪ 
TRPL: See 7.4.4.4 
▪ 
Ocular surface stains: See 7.4.4.5and 7.4.4.6 
▪ 
Ophthalmological evaluation: See 7.4.4.2 
▪ 
EA Assessment: See 7.4.4.2 
▪ 
Subject Diary Assessment: See más atrás 7.5.1.1 
▪ 
Adherence assessment: See más atrás 7.5.1.1 
▪ 
Subject continuity assessment: See más atrás 7.5.1.1 
▪ 
Return of PI and Subject Diary: refers to the return by the subject of the PI and the 
subject diary to the research center 7.5.1.1 . 
7.5.2 Unscheduled follow-up visits 
At the request of the patient or any other individual involved in the study, unscheduled follow-up 
visits may be conducted to report adverse events. During these visits, all relevant data on reported 
adverse events must be collected, and an appropriate management plan must be established, if 
applicable. 
7.6 Data collection 
7.6.1 Source documents 
Source documents are all written or printed records derived from automated processes (for 
example, printouts of laboratory results issued by automated analysis equipment) where 
information is first recorded and which become part of the patient's permanent record. Examples 
of source documents include medical records, clinical progress notes, laboratory reports, office 
study reports, nursing notes, follow-up notes, surgical records, etc. 
Researchers from participating centers and institutions are obliged to accept the monitoring of 
information related to the study, audits, review by ethics and research committees, and inspections 
by the health authority. This obligation implies direct access to source documents. 
7.6.2 Electronic forms of data collection 
All protocol-related data will be captured via an electronic case report form (ECF) by research team 
personnel. Protocol-related data should NOT be captured directly into the ECF; rather, they should 


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be transcribed from the corresponding source document. This procedure allows for monitoring to 
verify the information captured in the ECF. It is the investigator's responsibility to ensure the 
information is transcribed to the ECF correctly, completely, and in a timely manner. It is understood 
that all ECF forms captured and submitted for data analysis are approved by the investigator. 
7.6.3 Archive 
The data collected in this database is anonymous (only the patient number is stored along with other 
relevant information). The software used for data capture and storage meets the traceability 
requirements necessary for conducting clinical studies. The collected data will be stored by the 
sponsor or designated clinical research organization for a period of 10 years. Records of patient 
number assignment will remain at the participating institutions under the care of the PI or their 
team and must be safeguarded for at least 5 years. 
 
 


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8. Evaluation and management of 
adverse events 
8.1 Regulation and standards on adverse events 
The registration and reporting of adverse events will be carried out in accordance with the 
guidelines established in NOM-220-SSA1-2016, which is in accordance with the international ICH E6 
guidelines. 
8.2 Definition of adverse event 
According to the International Conference on Harmonization (ICH), an adverse event (AE) is any 
unfavorable medical occurrence in a patient undergoing clinical research who is administered a 
pharmaceutical product, regardless of causal attribution. 
Therefore, an AE may be any of the following: any unfavorable, unintended disease, symptom, or 
sign (including an abnormal laboratory finding) that is temporally related to the use of a medical 
product, whether or not considered to be related to that product; any new disease or exacerbation 
of an existing disease (worsening of the nature, frequency, or severity of a known condition); relapse 
of an intermittent medical condition (e.g., headache) not present at baseline; any deterioration in a 
laboratory value or other clinical test (e.g., electrocardiogram [ECG], x-ray) that is related to the 
symptoms or that results in a change in study or concomitant treatment or discontinuation of study 
drug. 
8.3 Definitions relevant to the classification of adverse events 
Severity (serious/non-serious), also called seriousness (serious/non-serious). A serious event is 
defined as any event that: results in death, threatens life, requires hospitalization or prolongs 
hospitalization, causes permanent or significant disability or incapacity, causes abnormalities or 
malformations in the newborn, or other medically significant conditions. 
Severity (mild, moderate, or severe). Mild conditions present with minimal symptoms and do not 
require treatment or discontinuation of medication; moderate conditions interfere with normal 
activities without threatening the patient's life, require treatment, and may or may not require 
discontinuation of medication; severe conditions interfere with normal activities and require 
pharmacological treatment and discontinuation of medication. 
Causality. This is the relationship assigned between the drug and the adverse event: certainly caused 
by the drug, there is clear evidence of causality, i.e. the adverse event reappears with the 
administration of the drug; probably caused by the drug, there is a high suspicion of causality but 
no direct evidence is available or it is considered unnecessary or dangerous, i.e. the reaction 
disappears when the drug is discontinued; possibly caused by the drug, there is additional 
information suggesting that the cause may be due to another drug or disease; unlikely to be caused 


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by the drug, there is a clear explanation for the origin due to the underlying disease or the use of 
another drug; conditional, there is a lack of data to issue a clear causality; unclassifiable, those for 
which, once all possible information on the adverse event has been obtained, it remains 
unclassifiable. 
8.4 Researcher Responsibilities 
The investigator is responsible for verifying the AE by conducting a questioning, reviewing the 
information recorded in the subject's diary, conducting a relevant physical examination, assessing 
progress, and providing appropriate medical and pharmacological management. The investigator is 
also responsible for monitoring the AE until it is resolved or resolved, and the patient is discharged, 
following the definitions established in national and international regulations.[43] [44] [45] 
In the event of an AE or any event that puts the health and well-being of the subjects at risk, 
appropriate medical care will be provided, either at the research center or by referring the subject 
to the highest-resolution hospital with which the research center has a medical care agreement. 
The PI will notify the sponsor's clinical monitor, in accordance with the timeframes established in 
national and international regulations. In the case of serious adverse events, the PI will notify the 
sponsor and record the corresponding information in the FERC, and in turn, will inform the IEC and 
the IC. 
The attention of the AE will be carried out according to the event attention diagram (see  
Figure 5Adverse event care). 
The final report prepared by the Clinical Team of the Clinical Operations Department of Laboratorios 
Sophia, SA de CV, will include adverse event reporting in compliance with current national and 
international regulations. [44] [43] 
If the research subject develops a chronic adverse event during their participation in the study, such 
as diabetes or arterial hypertension, they will be referred to a healthcare professional for chronic 
treatment. Follow-up and termination of participation will be in accordance with ICH guidelines. 
8.4.1 Recording of adverse events in the electronic case report form 
The EA registry considers: 
− 
Subject identification information such as: subject number, age, sex, and if applicable, 
specify the eye. 
− 
Information about the causality of the AE, its relationship to the PI, or to another study-
related drug, as appropriate. 
− 
Information on important dates: 
o Date on which the EA occurs 
o Date on which the IP is informed of the same 
o Date of resolution or outcome, as applicable. 
− 
Information on diagnosis and clinical management. 


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− 
PIs is detected , it must be reported as a serious adverse event within the timeframe 
stipulated by current regulations. The concomitant medications should include the therapy 
used for the pharmacological management of the adverse event. 
− 
Establish the outcome or resolution of the event: 
o Recovered/resolved without sequelae 
o Recovered/resolved with sequelae 
o Not recovered/Not resolved 
o Patient who died due to AE 
o Patient who died and it is judged that the drug may have contributed 
o Patient who died and this was not related to the product or drug under 
investigation, 
o A stranger 
− 
Information about the investigational product or medicinal product or the medicinal 
product associated with the AE, ADR or SRAM. As applicable, information concerning the 
generic name, distinctive name or code of the PI and/or investigational medicinal product 
must be recorded, as appropriate according to the methodological design of the study. This 
is relevant in the case of blinded studies or those where placebo is used as comparators, 
since there are circumstances that justify opening the blind to determine whether the 
adverse event can be attributable to the active agent, the combination of active agents, or 
to the pharmacologically inert substance(s), such as the vehicle or additives, as appropriate 
to the phase of clinical research in which the development of the medicinal product is 
located. It will also be necessary to record data concerning the batch number, 
manufacturing laboratory, expiration date, dose, route of administration, start and end 
dates of administration and/or consumption, reason for the prescription; depending on 
whether it is a product or medication under investigation (protocol in which the patient is 
currently participating) or a medication that the subject under investigation consumes for 
the treatment of concomitant underlying diseases or uses for the management of some 
temporary sign or symptom that does not correspond to the Natural History of the 
pathology that motivated his/her entry into the research protocol. 
− 
Indicate the withdrawal or continuation of the medication, as appropriate. Indicate whether 
the adverse event disappears upon withdrawal of the PI, investigational medication, or 
suspected medication (of causing the event). Also indicate whether a dose adjustment is 
made, if the event changes in intensity or severity, and if the reaction persists. It is important 
to indicate whether the AE reappears in subjects who are re-exposed to the medication 
after having been previously discontinued. 
− 
Information regarding concomitant pharmacotherapy. Indicate the generic name, dose, 
route of administration, start and end dates, and the reason for the prescription, regardless 
of whether it is in accordance with the prescribing information or the data sheet or if it is 
used outside of the regulations or as authorized by the local, national, or international 
regulatory body. 
− 
Information on relevant clinical history. The analysis of the AE considers the information 
previously described. However, the clinical context in which the adverse event occurs in the 
participants in the clinical research protocol is of particular interest. Therefore, information 
about previous conditions, hypersensitivity or allergy symptoms, previous surgical 


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procedures, laboratory tests or imaging examinations the participant has undergone, etc., 
that the researcher deems appropriate may be mentioned. 
8.4.2 Monitoring of adverse events 
The IP will provide care and follow-up to the AE presented by the participant until its outcome, in 
accordance with the provisions of the following section. 
8.4.3 Procedures for a serious adverse event 
The EA care process considers the following stages: 
 
Figure 5Adverse event care 
During the development and conduct of this study, undesirable adverse events or adverse reactions 
of medical significance may occur in the research subject, which are not necessarily causally related 
to the investigational medicinal products. These adverse events may occur during the use of 
investigational medicinal products at doses authorized for human use by a local, national, or 
Adverse Event 
Inform 
Appropriate care and 
treatment 
Categorization 
Preparation of medical notes 
Registration and notification to FERC 
At the research site. At a 1st-3rd level 
hospital (if required)  
By outcome: 
Serious/Not Serious 
By severity: 
Mild, moderate, or severe  
Physical 
examination and 
evaluation of the 
EA 
Not Serious EA 
Serious EA 
Follow up the EA 
until its outcome 
end 
+ Inform the sponsor within 
24 hours of becoming aware 
of it 
+ Follow up on the AE until 
its resolution 
+ Inform the IEC 
Notify: 
+ Clinical Safety 
Pharmacologist 
+ Pharmacovigilance 
Unit 
end 


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international regulatory body. However, it may be suspected that the investigational medicinal 
product or the investigational medicinal product may cause some undesirable clinical manifestation. 
AEs, ADRs, or SARs associated with one or more medicinal products may occur during the systematic 
evaluation of participants (on the days when clinical reviews are scheduled, according to the activity 
schedule) or suddenly, such that: 
1. The researcher should be the first person to whom the patient notifies that he or she 
has developed or experienced any harmful clinical phenomenon during his or her 
participation in this study. 
2. Based on their clinical judgment, the principal investigator will determine the 
appropriate treatment for the adverse event/reaction based on the relevant physical 
examination, history, etc., as well as the analysis of information available in the medical 
literature and the information contained in the investigator's manual, Prescribing 
Information, or the comparator drug's data sheet. 
3. This care may be provided at the research center or at the hospital with the highest 
capacity for treatment. Thus, if the patient is referred by the PI to a hospital, they will 
receive care through a referral system. The referral may be through a card identifying 
the subject as a study participant and linking them to the pre-established agreement 
with the institution, or through a referral medical note issued by the PI. Laboratorios 
Sophia, SA de CV, will pay the costs for medical care for participating patients when the 
adverse event is associated with or related to the PI or investigational drug. 
4. Taking into account the clinical information collected, either during the care provided 
at the research center or provided by the treating physician(s) at the hospital, the IP will 
record the AE in his/her clinical note, stating the seriousness, intensity (mild, moderate, 
or severe), and relationship with the product or drug under investigation. 
5. The PI must migrate the relevant data to the FERC and its respective adverse event 
section. In the case of serious adverse events, the clinical monitor of the study must be 
notified within 24 hours of becoming aware of them, so that they can then inform the 
Clinical Team and the UTFLS, and subsequently inform the IEC. Regarding non-serious 
adverse events, these will be recorded and appropriately addressed, and the 
corresponding regulatory body will be informed about the safety profile of the PI or 
investigational drug in the final clinical trial report. 
Recording the outcome of the AE depends substantially on the PI's follow-up of the subject, as most 
adverse events (see the safety profile section in section 5.3 and the investigator's manual) are 
expected to be ophthalmic in nature; however, systemic alterations may occur. Therefore, at the 
investigator's discretion, the participant's withdrawal or continuation will be considered. 
8.4.4 Assessment of causality 
Causality assessment is the methodology used to estimate the probability of attributing an observed 
adverse event to a medication. It considers probabilistic categories according to the available 
evidence and the quality of the information, based on national pharmacovigilance regulations. [43]  
The Pharmacovigilance and Technovigilance Unit of Laboratorios Sophia (UFTLS) can use the Karch 
and Lasagna algorithm, modified by Naranjo, referred to by Aramendi I, as a tool to facilitate the 
probabilistic categorization of causality. This algorithm scores different items, which allow a value 
to be assigned to the cause-effect relationship between the administration of the medication and 
the adverse reaction.  [46]See Table 3Karch and Lasagna algorithm modified by Naranjo. 


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No . 
Reagent 
Score 
Yea
h 
No 
1. 
There are conclusive previous reports on adverse drug reaction, adverse event or suspected adverse drug 
reaction 
+1 
0 
2. 
The adverse event occurred when the suspected drug was administered 
+2 
-1 
3. 
The adverse drug reaction, adverse event, or suspected adverse drug reaction improved upon 
discontinuation or administration of a specific antagonist 
+1 
0 
4. 
The adverse drug reaction/adverse event/suspected adverse drug reaction recurred upon administration of 
the investigational drug/investigational product/investigational drug 
+2 
-1 
5. 
There are alternative causes that can provoke this reaction. 
-1 
+2 
6. 
The adverse reaction/adverse event/suspected adverse drug reaction occurred after placebo 
administration 
-1 
+1 
7. 
The drug was determined in blood or other fluids in toxic concentrations 
+1 
0 
8. 
The intensity of the adverse reaction/adverse event/suspected adverse drug reaction was greater with 
higher doses or less with lower doses 
+1 
0 
9. 
The patient has had similar reactions to the investigational drug/product or investigational drug in the past 
+1 
0 
10. 
The adverse reaction/adverse event/suspected adverse drug reaction was confirmed with some objective 
evidence 
+1 
0 
Total score 
summation 
Probabilistic category based on the score obtained 
Yo 
The causal relationship is verified 
≥ ,9 
II 
The ADR is likely due to the investigational drug or product 
5 to 8 
III 
The ADR may be due to the investigational drug or product 
1 to 4 
IV 
The causal relationship is doubtful 
0 
Each reagent receives a defined score and the final sum allows estimating the probabilistic category of the cause-effect 
relationship between the administration of the investigational product and the adverse reaction, adverse event or suspected 
adverse reaction. 
Table 3Karch and Lasagna algorithm modified by Naranjo 
Thus, the degree of certainty required to establish the PI as the causal agent of the harmful 
phenomenon occurring to the subject of the clinical study is determined. This can also be indicated 
directly by the PI based on their clinical experience or through the voluntary application of the 
aforementioned tool. However , it is important that the researcher and the UFTLS consider the 
following arguments in favor of a causal relationship: 
a) Strength of association, which refers to the number of cases in relation to those exposed. 
b) The consistency of the data, that is, the presence of a common characteristic or pattern. 
c) The exposure-effect pattern, which determines the relationship with the site of onset, time, 
dose and reversibility after suppression. 


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d) Biological plausibility, which refers to the possible pharmacological or pathophysiological 
mechanisms involved in the development or presentation of the adverse event. 
e) Experimental findings, for example, the appearance of anomalous metabolites or high levels 
of drug or its biotransformation product. 
f) Analogy, which refers to the experience acquired with other related drugs, adverse 
reactions frequently produced by the same family of pharmacological agents. 
g) Nature and characteristics of the data, i.e. objectivity, accuracy and validity of the relevant 
documentation. [47]  
8.5 Unanticipated problems 
Unanticipated problems (ANP) are considered situations that pose risks to the participating 
subjects, generally any incident, experience or result that meets all of the following criteria: 
• 
Unexpected in terms of its nature, severity, or frequency in relation to: 1) study-related 
documents such as the investigator's manual, study protocol, and informed consent form; and 
2) the characteristics of the study population. 
• 
Related or possibly related to your participation in the study (possibly related means that there 
is a reasonable possibility that the incident or results were caused by study procedures). 
• 
Indication that the research places participants at greater risk of harm (including physical, 
psychological, economic, or social) than previously recognized. 
8.5.1 PNAs Report 
The PI will be responsible for reporting PNAs to the sponsor, the IC, and the IEC. The report should 
contain the following information: 
• 
Study identification: protocol title and number, name of the PI and, where applicable, the 
center. 
• 
Detailed description of the event, incident, experience or outcome. 
• 
Explanation, justification of the reasons why the incident represents a PNA. 
• 
Description of changes to the protocol or corrective actions taken or proposed in response to 
the NAP. 
PNAs that are EAS must be reported to the IEC and the sponsor within the first 24 hours of the IP 
becoming aware of them. 
Any other PNA will be reported to the IEC and the sponsor within the first 5 business days after the 
IP becomes aware of it. 
 
 


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9. Study monitoring 
The study sponsor is responsible for monitoring the study. Monitoring activities include, but are not 
limited to: general safety monitoring, general study quality monitoring, study site monitoring, 
adverse event detection monitoring, reporting and follow-up, monitoring to resolve data entry 
discrepancies, etc. 
Responsibility for monitoring activities and ultimate responsibility for monitoring rests with the 
sponsor. 
The details of the monitoring activities are specified in a separate document from this protocol in a 
Monitoring Plan. 
9.1 Monitoring of study centers 
The research centers participating in the study will be monitored. At least one initial visit and one 
closing visit must be conducted for each center, although one or more follow-up visits may be 
required between these two mandatory visits. 
The initial visit must be conducted before the first participant is enrolled at that center. During this 
visit, the monitor will verify that the materials to be used during the study have been received and 
that the personnel involved in study activities have been trained in the study. The monitor will also 
verify compliance with applicable regulatory requirements and standard operating procedures. 
At the follow-up visit(s), the monitor will review the study documents to confirm that the research 
protocol and applicable standard operating procedures are being followed, that data entry is 
complete and timely, and that adverse event reporting is being conducted appropriately. At each 
visit, the monitor will discuss the findings with the investigator, and the investigator will determine 
the appropriate actions to be taken. 
The closing visit will take place at the end of the study, once the last participant at the site has been 
discharged from follow-up. During this visit, the monitor will verify that the site has all the necessary 
documentation for archiving, that all biological samples have been sent for analysis, that all study 
drug (used and unused) has been recovered and sent to the sponsor, and that all unused materials 
have been retrieved. 
Details of monitoring are set out in the relevant plan. 
9.2 Audit and quality control 
To ensure compliance with GCPs and all applicable regulatory requirements, Laboratorios Sophia, 
SA de CV may conduct quality assurance audits. Regulatory agencies may also conduct a regulatory 
inspection of this study. 
Details of the audit process are set out separately in an Audit Plan. 


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9.2.1 Pre-study audit 
The study centers included in the study will be subject to a feasibility visit prior to center selection, 
where they will be verified to meet the minimum requirements indicated by the sponsor. 
9.2.2 Audit during the conduct of the study 
They may take place at any time before, during, or after the conclusion of the study. If an audit or 
inspection is conducted, the investigator and the institution must agree to allow the 
auditor/inspector direct access to all relevant documents and must allocate their time and staff time 
to the auditor/inspector to discuss the findings and any pertinent issues. If the audit has not been 
scheduled by the sponsor, the center must notify Laboratorios Sophia, SA de CV immediately. 
 
 


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10. Statistical analysis 
10.1 
Data analysis 
10.1.1 Statistical analysis 
Statistical analysis will be performed by staff of Laboratorios Sophia, SA de CV. The statistical 
program SPSS version 19.0 (IBM Corporation, Armonk, NY, USA) will be used. 
The designated personnel will be blinded to the intervention groups. Coding will be performed using 
consecutive numbers for each intervention group. 
The data will be collected and organized in an Excel spreadsheet (Microsoft® Office). The data will 
then be exported to the SPSS software platform. The variables will be categorized according to their 
nature (see Table 2). 
10.1.2 Data interpretation 
The Kolmogorov-Smirnov and Shapiro-Wilk tests will be performed, as applicable, to determine 
whether the distribution is normal in the results obtained in each study group. 
The results of continuous quantitative variables will be presented in measures of central tendency: 
mean, standard deviation and ranges. 
The statistical analysis of continuous quantitative variables to find significant differences ( p<0.05 ) 
will be as follows: 
• 
Intra-group analysis: will be determined using the Wilcoxon rank test for quantitative 
variables. 
 
• 
Between-group analysis: Differences between groups will be analyzed using the Student t-
test or the Mann-Whitney U statistic if applicable ( it will be used to test whether a group 
of data comes from the same population). 
 
The level of difference considered significant will be an alpha (α) of 0.05 or less. A 95% CI will be 
considered for noninferiority criteria. 
The results of the nominal and ordinal qualitative variables will be presented in frequencies, 
proportions and percentages. 
Statistical analysis to identify significant differences in qualitative variables will be performed by 
creating 2x2 contingency tables and will be carried out as follows: 
 
• 
Intra-group difference: McNemar's test. This test is applied to 2x2 contingency tables with 
a dichotomous trait, with matched pairs of subjects, to determine whether the marginal 
frequencies of the row and column are equal (marginal homogeneity). 
 


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• 
Difference between groups: Pearson's Chi-square test ( X 2 ) or Fisher's exact test for 
expected values less than 5. 
 
The level of difference to consider significance will be an alpha (α) of 0.05 or less. 
For adverse event reporting, all eyes of participants randomized to an intervention group after the 
baseline visit will be considered. Results will be expressed as the number of subjects. 
The final results report will be displayed in tables or graphs, as appropriate. 
10.1.3 Procedure for handling missing data 
Safety: The safety assessment will include in the analysis all subjects (both eyes) who have been 
exposed at least once to any of the interventions. Subjects enrolled in the efficacy phase will be 
included in the safety analysis for this phase, regardless of the visit at which they were eliminated 
from the study (ITT; intention-to-treat population). 
Efficacy: Subjects who meet a minimum adherence of 70% will be included in the statistical analysis 
to meet the study objective, based on the weight of the PI. In cases where the container is not 
returned or has not been physically intact, adherence will be measured using the subject's diary. 
10.1.4 Deviations from the statistical analysis plan 
According to the sample size calculation to meet the efficacy objective, 102 evaluable subjects (51 
subjects per arm) are required. If this number is not met due to a loss of subjects exceeding the 20% 
threshold established in this protocol (loss to follow-up or withdrawal from ICF), as mentioned in 
section 5.3.1, in order to balance the treatment groups, the sponsor may substitute these subjects. 
The results obtained from the replaced subjects will continue to be used for safety analysis and will 
be part of the ITT. 
10.1.5 Subjects included in the analysis 
A preliminary safety analysis will be performed upon completion of follow-up of subject 12 in the 
Nanodrop® group (Phase I). 
If fewer than 20% of unexpected drug-related AEs occur in the Nanodrop® group, enrollment for 
the efficacy analysis (Phase II) will be completed. Otherwise, the study will be terminated. 
For phase II of the study, those subjects who meet a minimum adherence of 70% will be included in 
the statistical analysis to meet the study objective (PP; per-protocol population). 
10.2 
Sample size calculation 
10.2.1 Number of subjects calculated 
n= 126 evaluable subjects (both eyes) 
63 subjects per arm. 


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An estimated 63 subjects (both eyes) are enrolled per treatment arm. During the safety phase, 
24 subjects (12 from each group) will be recruited, and 102 will be recruited during the final 
phase, completing the sample of 126 required for the efficacy analysis. 
10.2.2 Justification of the sample calculation 
For the sample size calculation, studies with ocular lubricants in patients with dry eye were 
considered, in which changes in the OSDI score were the primary outcome variable. 
Nanodrop® is expected to be non-inferior to its comparator (Systane® Balance), based on the 
following working hypotheses: 
H 0 : ε > δ 
H 0 : ε ≤ δ 
Where μ A - μ B = ε is the true difference in means between the test treatment (PRO-176) and the 
active control (Systane® Balance). Where δ is the non-inferiority margin, and the ratio of the sample 
sizes between the two groups is given by:  
𝑘= 𝑛𝐴
𝑛𝐵
 
Calculations were performed using non-inferiority equations for two means and for statistical 
power. [48, 49]  
 
𝑛𝐴= 𝑘𝑛𝐵 𝑦 𝑛𝐵= (1 + 1
𝑘) (𝜎
𝑧1−𝛼+ 𝑧1−𝛽
𝜇𝐴−𝜇𝐵−𝛿)
2
 
 
1 −𝛽= 𝜃(𝑧−𝑧1−𝛼) + 𝜃(−𝑧−𝑧1−𝛼)  ,𝑧=
𝜋𝐴−𝜋𝐵−𝛿
𝜎√
1
𝑛𝐴+ 1
𝑛𝐵
 
 
Where; σ is the standard deviation, k = n A / n B is the coincidence ratio, θ is the standard Normal 
distribution function, α is the type I error (confidence interval), β is the type II error (meaning that 
1-β corresponds to the power) and δ is the test margin. 
With a power of 80% (β=0.20), a significance level of 0.05 (α) and a non-inferiority margin (δ) of -5 
points on the OSDI score. 
The sample size calculation was performed considering a reduction in the OSDI score of 17.6 points 
for the placebo group at their final visit versus a reduction of 16.5 points for the treated group. 
Considering a σ of 17.1, a similar reduction in the OSDI score is expected for both treatments, with 
no statistically significant differences at their final visit. [50, 51, 52, 53] 
 
 


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11. Ethical considerations 
11.1 
Approval of the committees 
This study will be conducted in accordance with the standards of the Declaration of Helsinki, World 
Medical Association 2013. Nuremberg Code; Nuremberg Judgment by the International Tribunal of 
Nuremberg, 1947. Belmont Report, National Commission for the Protection of Subjects of 
Biomedical Research and Conduct, 1979. It will be conducted in accordance with the scientific and 
technical requirements necessary for the registration of medicines for human use of the 
International Conference on Harmonization (ICH) Guide to Good Clinical Practice. International 
Ethical Guidelines for Biomedical Research Involving Human Subjects of the Council for International 
Organizations of Medical Sciences (CIOMS, 2002). International Ethical Guidelines for 
Epidemiological Studies of the Council for International Organizations of Medical Sciences (CIOMS, 
2008). The Research Ethics Committee and the Research Committee will evaluate the protocol 
before conducting the study and will issue their approval or any possible modifications for its 
implementation. These Committees must be notified of any significant changes to the protocol. In 
addition to the above, the current regulations of the regulatory authority must also be complied 
with. 
The sponsor's authorized personnel will submit the essential documentation of the research project 
for evaluation by the Research Ethics Committees, Research Committees, and when applicable, to 
the Biosafety Committee: research protocol, informed consent form, researcher's manual, patient 
materials, as well as other additionally requested documents, in accordance with the local, national 
or international requirements applicable by regulatory entities. 
The study will not be initiated at the research center without the confidentiality agreements and 
financial proposals from each of the principal investigators, duly signed, and without having 
previously obtained the favorable opinion and/or approval of the corresponding Research Ethics 
Committees, Research Committees, and, where applicable, the Biosafety Committee. 
The study will not begin without meeting the relevant local, national, or international regulatory 
requirements and obtaining the appropriate health authorization. 
The study is considered as research with greater than minimum risk, in accordance with the 
Regulations of the General Health Law on Health Research, Second Title, Chapter I, Article 17, 
Section III, published in the Official Gazette on January 6, 1987 3 
11.2 
Amendments to the protocol 
The amendment process will be relevant when there is a need to make any changes to a document 
that is part of the research project or protocol, due to changes in the methodological structure, 
replacement of the principal investigator, or the identification of risks to the research subjects. 
Documents that may be amended include: the protocol, informed consent letter, researcher's 
manual, patient documents, measurement scales, and activity schedule. 


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Any amendment must be approved by the sponsor and/or the principal investigator. The amended 
document(s), once reviewed and approved by the Research Ethics Committee and the Research 
Committee or, when applicable, by the Biosafety Committee (entities that issued the initial 
favorable opinion for the conduct of the research), will be sent for authorization by the relevant 
regulatory entity. 
Amendments that substantially modify the protocol or impose additional or different risks on 
research subjects must be approved by the aforementioned Committees. It is the investigator's 
responsibility to take measures in situations requiring immediate action to prevent unnecessary 
harm to study participants. 
The principal investigator is responsible for communicating to the Research Ethics Committee any 
amendments to the protocol that could affect the rights, safety, or well-being of the research 
participants. Likewise, they must report any situation or new knowledge that indicates an increased 
risk to participants, the premature termination or suspension of the study, the reasons for this, and 
the results obtained to that point. They must also report the conclusion of the study upon 
completion of the research protocol. 
11.3 
Early termination of study 
The study may be temporarily suspended or terminated prematurely if there is sufficiently 
reasonable cause. Written notification documenting the reason for the suspension or early 
termination must be provided by the party executing the suspension. The PI must promptly inform 
the study participants, the IC, and the IRB, providing the reasons. 
Situations in which suspension or early termination of the study will be considered include, but are 
not limited to: 
1. 
The presence of serious adverse events in more than 10% of participants in a study 
group. 
2. 
The regulatory authority (COFEPRIS) considered it due to security alerts. 
3. 
The Sponsor determines this for its convenience or eventualities such as: financial 
support, manufacturing errors, etc. 
4. 
The determination of unexpected risks to participants that are significant or 
unacceptable. 
5. 
Obtaining new relevant safety information. 
6. 
Insufficient adherence to protocol requirements. 
7. 
The data obtained are not evaluable or are not sufficiently complete. 
8. 
The determination that the primary objective has been achieved. 
9. 
The determination of futility. 
In the event of suspension, the study may be resumed once the situations that led to the suspension 
have been resolved, provided this justification is sufficient for the sponsor, IC, IEC, and regulatory 
authorities. 


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11.4 
Informed consent 
The informed consent letter contains complete and understandable information about the study 
and the investigational product, in accordance with current applicable regulations and Good Clinical 
Practices. 
The informed consent letter will be considered a source document and will be filed as such. The 
site's principal investigator is responsible for ensuring that all new versions of the informed consent 
form undergo the appropriate approvals (the same ones that the original informed consent form 
underwent) and that the most current approved version is presented to the study subjects. 
11.4.1 Obtaining 
Informed consent must be obtained before the subject undergoes any procedure indicated in the 
protocol. For this purpose, the informed consent form must be signed. 
Written consent documents will incorporate the elements of informed consent described in the 
Declaration of Helsinki and the ICH Guidelines for Good Clinical Practice and will be in compliance 
with all applicable laws and regulations. 
The IP will provide the potential participant with all information regarding the characteristics of the 
study, its potential benefits, risks, objectives, and procedures. 
This information will be provided in a language the subject understands. The subject will be 
explained that they have the right to discontinue their participation in the study at any stage, 
without affecting their relationship with the researcher and/or their future participation. Informed 
consent will be presented to the potential participant; they must have sufficient time to review each 
and every aspect mentioned above. Any questions they may have will be clarified by the person 
responsible for obtaining informed consent. 
Once the participant agrees to participate in the study, he or she must sign and date the informed 
consent letter in the presence of two witnesses, whether or not related to the study subject. These 
witnesses will participate in the informed consent process and sign, confirming that the process was 
carried out prior to any study procedure, that the study information was clearly explained, and that 
any questions were clarified. 
In the event that a subject is illiterate, acceptance will be with his or her fingerprint, and in the event 
that the subject is not capable of providing adequate written informed consent, a “legally 
authorized” representative of the subject may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The IP must also sign and date this consent. 
Informed consent must be signed in duplicate by all participants and two witnesses. One copy will 
be filed in the researcher's folder and the other will be given to the participant. The PI or designated 
staff member must document the process of obtaining informed consent through a detailed medical 
note, specifying the signed version, the date the document was signed, and how the process was 
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11.4.2 Special considerations 
The procedures that will be performed during the conduct of the study do not pose any additional 
risk that should be considered apart from the procedures listed in the informed consent. 
11.4.3 Modifications to informed consent 
Any change to the “informed consent” constitutes an amendment to this document and must be 
submitted for approval to the Research Ethics Committees and, if applicable, to the Competent 
Authorities. 
Such amendments may be implemented only after obtaining written approval from the Research 
Ethics Committee and the Regulatory Body (as applicable), except for an amendment that is 
required to eliminate an immediate danger to the study subjects. 
A re-consent process must be conducted for each subject affected by the amendment under the 
same conditions as those described above (see section 12.4.1) to ensure that the subject is promptly 
informed of the new information contained in the document. The subject will be given a signed 
original of the amendment, and the researcher will retain the second original. 
11.5 
Confidentiality 
All documents and information provided to the research center by the sponsor are strictly 
confidential. The PI expressly agrees that the data regarding his or her professional and clinical 
experience, provided to the sponsor in paper form and stored electronically, are solely for use in 
connection with his or her activities with the clinical study sponsor, in accordance with Good Clinical 
Practice. 
The researcher agrees that he and his team members will use the information only within the 
framework of this study, to carry out the protocol. This agreement is binding as long as the 
confidential information has not been publicly disclosed by the sponsor. 
The clinical study protocol provided to the investigator may be used by the investigator and his or 
her team to obtain informed consent from the subjects for the study. The clinical study protocol, as 
well as any information derived from it, must not be disclosed to other parties without the sponsor's 
written authorization. 
The researcher will not disclose any information without the prior written consent of Laboratorios 
Sophia, SA de CV, except to representatives of the Competent Authorities, and only at their request. 
In the latter case, the researcher is obligated to inform Laboratorios Sophia, SA de CV before 
disclosing the information to these authorities. 
The researcher will complete and maintain a subject selection record, as well as the identification 
and enrollment list of each subject participating in the study. The researcher agrees to grant on-site 
access to the auditor and/or representatives of the Competent Authorities. The information will be 
treated in compliance with professional secrecy. 
All FERCs and communications related to study subjects will identify them only by their study subject 
identification number. The information collected in this study will be exchanged between the 


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sponsor and the research site and must be treated confidentially. The Health Authority, the IRB, the 
IC, the sponsor, the monitors/auditors, and third-party auditors will be the only bodies authorized 
to review study documentation. If publications arise from this research project, under no 
circumstances will they contain information about the identification of study subjects. If the study 
results are published, no personal information about the study subjects will be revealed. 
The protection of personal data will be in accordance with the corresponding current regulations. 
11.6 
Conflict of interest 
The independence of the study's conduct and results from any actual or perceived external 
influences is critical. Therefore, any current conflict of interest of any person playing a role in the 
design, conduct, analysis, publication, or any other aspect of this study will be declared. 
Furthermore, those with a perceived conflict of interest will be asked to manage it in a manner 
appropriate to their participation in the study. 
11.6.1 Declaration of interests 
The IP undertakes to make a declaration of financial interests, as well as conflict of interests prior 
to the start of the study. 
11.7 
Access to information 
The final study database will be the property of Laboratorios Sophia, SA de CV, and access to it will 
be restricted. The PI will not have access to it except with prior written authorization from the 
sponsor. 
Any information obtained that is relevant to the safety of the subjects participating in the study 
must be immediately shared with the research center, so that the study subjects can be notified. 
11.8 
Ancillary and post-study care 
Once the study is completed and adverse events are closed according to section 8, the sponsor will 
not extend care to the research subject. 
 
 


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12. Biosecurity aspects 
NO BIOSECURITY IMPLICATIONS 
This protocol, with title: “ Phase I-II clinical study to compare the safety and efficacy of 
Nanodrop® versus Systane® Balance in the treatment of patients with dry eye”, and number: 
SOPH176-1218/I-IIDOES NOT HAVE BIOSECURITY IMPLICATIONS, since infectious-contagious 
biological material will NOT be used; pathogenic strains of bacteria or parasites; viruses of any 
type; radioactive material of any type; genetically modified animals and/or cells and/or plants; 
toxic, hazardous or explosive substances; any other material that puts the health or physical 
integrity of the research center staff or research subjects at risk or affects the environment. 
Likewise, it is declared that no cell, tissue or organ transplant procedures, or cell therapy will be 
carried out in this project, nor will laboratory, farm or wildlife animals be used. 
 
 


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13. Publication Policy 
13.1 
Final report 
Once the statistical analysis is completed, the final report will be written with the results obtained, 
by the Clinical Team of the Clinical Operations Department of Laboratorios Sophia, SA de CV. This 
report will be prepared following the recommendations of the ICH E3 Step 4 Guide. 
13.2 
Communication of results 
Regardless of the results of the study, Laboratorios Sophia, SA de CV, is committed to 
communicating the final study report to the principal investigators and COFEPRIS. These results will 
also be shared with the research committee and the IEC. The PI will be responsible for 
communicating the results to the research subjects. 
Laboratorios Sophia, SA de CV will retain at all times the rights to the publication and dissemination 
of the information contained herein. 
13.3 
Publication of the results 
Laboratorios Sophia, SA de CV, acting as the sponsor of the study, assumes full responsibility for its 
role and retains exclusive ownership rights to the study results, which it may use as it sees fit. 
The PI agrees not to publish or communicate data collected from the study, unless prior written 
agreement is obtained from Laboratorios Sophia, SA de CV. Any manuscript derived from the data 
obtained with this protocol must be submitted for review by the sponsor before any attempt to 
submit it for publication in any journal or scientific conference. 
However, if the sponsor is in the process of filing a patent application on the results of the study, 
the sponsor may delay publication or communication of the results of the study until the date of 
registration or when it deems appropriate. 
Authorship assignments for publications are the sponsor's responsibility. However, express 
authorization from those invited to participate as authors is required. Authors have the right to 
review the manuscript prior to publication, as well as to provide comments and suggestions. Such 
comments must be submitted within the first 15 calendar days of receipt of the project. 
 
 


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14. Financing and insurance 
14.1 
Compensation to study participants 
Subjects participating in the study will not receive financial compensation for their participation. 
However, randomized subjects will receive financial support in the form of travel expenses for each 
scheduled visit they attend on time. This support, as well as the amount, will be specified in the 
informed consent form. 
14.2 
Insurance for study participants 
Subjects participating in the study will sign the informed consent form, which specifies that 
Laboratorios Sophia, SA de CV agrees to pay for immediate treatment resulting from injuries or 
illnesses caused by the investigational products until resolved, in accordance with medical 
judgment. 
All study participants will be covered by a liability insurance policy contracted by Laboratorios 
Sophia, SA de CV. Information on the policy will be made available to the research centers. In the 
event of a medical emergency, the research center must have the personnel, materials, equipment, 
and procedures in place for immediate management. 
 
 
 
 


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15. Annexes 
15.1 
OSDI 
 
SOPH176-1218/I-II
/
/
Iniciales del sujeto:
No. de sujeto: 176-______-_____
Indicaciones:
Subtotal de las celdas contestadas
(A)
Subtotal de las celdas contestadas
(B)
Subtotal de las celdas contestadas
(C)
Suma de A+B+C =
(D)
Número de reactivos contestados, no incluya las respuestas como NA
(E)
Versión 1.0                                                                                                                                                                     07/Feb/19
NA
NA
NA
NA
NA
NA
NA
Frecuencia
En ningún 
momento
En todo 
momento
Casi en 
todo 
momento
10. Viento
4
3
2
1
0
11. Lugares con baja humedad 
(secos)
4
3
2
1
0
Durante la última semana,
¿Ha sentido incomodidad en 
los ojos con alguna de las 
siguientes situaciones?
En todo 
momento
Casi en 
todo 
momento
El 50% del 
tiempo
Casi en 
ningún 
momento
En ningún 
momento
Frecuencia
7. Conducir de noche
4
3
2
1
0
8. Trabajar con computadora o 
un cajero automático
4
3
2
1
0
El 50% del 
tiempo
Casi en 
ningún 
momento
NA
NA
3
2
1
0
4. Visión borrosa
5. Mala visión
4
3
2
1
0
4
3
2
1
0
4
3
2
1
0
4
Durante la última semana,
3
2
1
0
4
3
12. Zonas con aire 
acondicionado
4
3
2
1
0
9. Ver televisión
4
3
2
1
0
2
1
0
¿Ha tenido problemas  en los 
ojos que le han limitado a 
realizar estas acciones?
6. Leer
4
1. Sensibilidad a la luz
¿Ha experimentado alguna de 
las siguientes alteraciones?
Frecuencia
2.  Sensación de arenilla en los 
ojos
3. Dolor de ojos
El test OSDI es un test sencillo creado para establecer una gravedad/ clasificación del ojo seco según su
sintomatología. Conteste a las siguientes preguntas marcando la casilla que mejor represente su respuesta:
OSDI (Ocular Surface Disease Index)
No. de estudio:
Fecha: 
Ficha de identificación
En ningún 
momento
Casi en 
ningún 
momento
El 50% del 
tiempo
Casi en 
todo 
momento
En todo 
momento
Durante la última semana,


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15.2 SICCA CTO format 
 
Verde lisamina 
(solo conjuntiva) 
Grado      Puntos 
0 
0-9 
1 
10-32 
2 
33-100 
3 
>100 
Fluoresceína 
(solo córnea) 
Grado      Puntos 
0 
0 
1 
1-5 
2 
6-30 
3 
>30 
Formato de Calificación de Tinción Ocular del SICCA 
Puntos adicionales para la tinción de 
fluoresceína solamente: 
+1 si hay parches de tinción confluente  
+1 si hay tinción en el área pupilar          
+1 si hay filamentos                                    
SOPH176-1218/I-II
/
/
Iniciales del sujeto:
No. de sujeto: 176-______-_____
No. de estudio:
Fecha: 
Ficha de identificación
Verde lisamina 
(solo conjuntiva) 
Grado      Puntos 
0 
0-9 
1 
10-32 
2 
33-100 
3 
>100 
Fluoresceína 
(solo córnea) 
Grado      Puntos 
0 
0 
1 
1-5 
2 
6-30 
3 
>30 
Puntos adicionales para la tinción de 
fluoresceína solamente: 
+1 si hay parches de tinción confluente  
+1 si hay tinción en el área pupilar          
+1 si hay filamentos                                    
OD 
OS 
 
Puntaje Córnea:__________ 
 
Puntaje Conjuntiva:________ 
  
Puntaje Córnea:__________ 
  
Puntaje Conjuntiva:________ 
Versión 1.0 
 
 
 
 
 
 
 
07/Feb/19 


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SAP_001.pdf: 
Phase  I-II  clinical  study  to  compare  the  safety  and  efficacy  of  
Nanodrop®  versus  Systane®  Balance  in  the  treatment  of  patients  with  
dry  eye.
8.0
Objectives  of  the  Study.................................................................................................................  2
9.0
References........................................................................................................................  11
Design  of  Study  SOPH176-1218/I-II................................................................................  2
3.0
4.0  Sample  Size ................................................................................................................  4
10.0  Annexes................................................................................................................................  12
Sample  Size  Calculation..................................................................................................  4
5.0
1.0
Abbreviations..............................................................................................................................  2
7.0  Analysis  Methods ................................................................................................................  8
Changes.................................................................................................................................  10
2.0
Protocol  Code:  SOPH176-1218/I-II
Content
Protocol  Version:  2.0
Creation  date:  January  2019.
Page  1  |  13
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
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3.0  Study  Design  SOPH176-1218/I-II
2.0  Objectives  of  the  Study
1.0  Abbreviations
3.1  Duration  of  treatment
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Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
EA
Ocular  Surface  Disease  Index
MAVC
Adverse  events
Tear  break-up  time
Informed  Consent
Population  by  protocol
OSDI
To  evaluate  the  safety  of  ophthalmic  application  of  Nanodrop®  by  quantifying  the  incidence  of  unexpected  Adverse  
Events  (AEs)  related  to  the  investigational  product  (IP).
Intention-to-treat  population
TRL
V1
CI
Best  corrected  visual  acuity
Initial  visit
VF
ITT
Research  Product
MC
Security  (Phase  I):
PRO-176  Nanodrop®
PI
Efficacy  (Phase  II):
Electronic  Case  Report  Form
Safety  call
Follow-up  visit  1
PP
VB
To  demonstrate  the  non-inferiority  of  Nanodrop®  compared  to  Systane®  Balance  in  the  treatment  efficacy  of  patients  with  
dry  eye,  using  the  OSDI  (Ocular  Surface  Disease  Index)  test  score.
Phase  I-II,  comparative,  non-inferiority,  active-controlled,  parallel-group,  double-blind,  randomized  clinical  trial.  Safety  
analysis  comparing  the  visits  of  the  first  12  patients  in  the  Nanodrop®  group.  If  fewer  than  20%  of  unexpected  adverse  
events  (AEs)  related  to  the  investigational  product  occur,  recruitment  continues  until  the  sample  for  the  efficacy  analysis  
is  complete.
CRF
Concomitant  medication
LLS
Final  visit
30  days.
Machine Translated by Google


CI:  Informed  Consent;  BCVA:  Best  Corrected  Visual  Acuity;  OSDI:  Ocular  Surface  Disease  Index;  AE:  Adverse  Event;  
PI:  Investigational  Product;  MC:  Concomitant  Medication.
Page  3  |  13
X
Delivery  of  PI  and  start  of  
intervention
X
D  31  to  +  1
D  1
X
X
subject
X
X
X
X
X
MC  Evaluation
X
Procedures
PI  Assignment
VB
Ocular  surface  stains
Continuity  assessment  of  the
Return  of  PI  and  Subject's  Diary
VF
Ophthalmological  evaluation
Delivery  of  patient  materials  
and  instructions  for  completion  
(Subject  Diary)
Table  1.  Study  schedule
Medical  record
X
X
X
X
X
X
X
subject
EA  Assessment
Adherence  assessment
D  37  ±  1
MAVC
X
X
D  8
Tear  film  break-up  time  with  
fluorescein
Evaluation  of  the  Diary  of  the
X
CI  Signature
X
X
X
X
Delivery  of  the  PI  and  start  of  
intervention
V1
X
X
X
X
X
X
X
X
comprehensive
Urine  pregnancy  test
Eligibility  criteria
X
LlS
X
X
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
Machine Translated by Google


Figure  1.  Suggested  workflow.  ITT:  Intention-to-treat  population;  PP:  Per-protocol  population.
PRO-176  (Nanodrop®;  Laboratorios  Sophia,  SA  de  CV)  is  expected  to  be  non-inferior  to  its  comparator  
(Systane®  Balance;  Alcon  Research  Ltd,  Fort  Worth,  TX,  USA),  according  to  the  following  working  
hypotheses:
For  the  sample  size  calculation,  changes  in  the  OSDI  (Ocular  Surface  Dehydration  Index)  questionnaire  
score  were  considered,  in  studies  with  ocular  lubricants  in  patients  with  dry  eye  disease  (DED ),  as  the  
primary  efficacy  variable.
An  estimated  63  subjects  (both  eyes)  per  treatment  arm  are  planned  (Phase  I:  12  subjects /  Phase  II:  114  
subjects).
Where  ÿA  -  ÿB  =  ÿ  is  the  true  difference  in  means  between  the  test  treatment  (PRO-176)  and  the  active  
control  (Systane®  Balance).  Where  ÿ  is  the  non-inferiority  margin,  and  the  ratio  of  the  sample  sizes  
between  the  two  groups  is  given  by:
Calculations  were  performed  using  the  non-inferiority  equation  for  two  means  and  for  statistical  power  
(Chow  et  al.,  2008).
1ÿ
2
1
+
=
=
5.0  Sample  Size  Calculation
1:  >
0:  ÿ
4.0  Sample  Size
Page  4  |  13
=  (1  +
)  ( 1ÿ  ÿ  ÿ )
Version  3.0
1  ÿ  =  ( ÿ
Statistical  Analysis  Plan
SOPH176-1218/I-II
) ,
=
)  +  (ÿ  ÿ
1ÿ
ÿ  1
1ÿ
ÿ  ÿ
+
1
Machine Translated by Google


Primary  Safety  outcome  variable:
Primary  efficacy  outcome  variables:
•  Incidence  of  unexpected  adverse  events  (AEs)  related  to  the  drug.
•  OSDI  test  score.
With  a  power  of  80%  (ÿ=0.20),  a  significance  level  of  0.05  (ÿ)  and  a  non-inferiority  margin  (ÿ)  of  -5  points  on  the  OSDI  score  
(Grubbs  et  al.,  2014;  Labetoulle  et  al.,  2017;  Pérez-Balbuena  et  al,  2016).
Where;  ÿ  is  the  standard  deviation,  k=nA/nB  is  the  agreement  ratio,  ÿ  is  the  standard  Normal  distribution  function,  ÿ  is  the  
type  I  error  (confidence  interval),  ÿ  is  the  type  II  error  (meaning  that  1-ÿ  corresponds  to  the  power)  and  ÿ  is  the  test  margin.
Secondary  efficacy  outcome  variables:
The  calculation  was  based  on  the  study  by  Benitez-Del-Castillo  et  al.,  2016.  Phase  I  and  II  clinical  study.  A  total  of  156  
healthy  subjects  and  patients  with  DED  were  enrolled.  The  Phase  I  study  included  30  healthy  volunteers;  it  was  a  single-
center,  parallel-group,  open-label  study.  Phase  II  was  a  multicenter,  double-blind  study.  In  Phase  I,  SYL1001  was  administered  
at  1.125%  and  2.25%  doses,  and  in  Phase  II,  at  0.375%  and  0.75%.  After  10  days  of  treatment,  the  primary  efficacy  variable  
was  the  effect  on  the  OSDI  score.  OSDI  scores  were  significantly  reduced  compared  to  baseline  (p<0.01)  for  all  treatments  
in  both  Phase  I  and  Phase  II.  No  statistical  differences  were  observed  between  treatments.
•  Changes  in  best  corrected  visual  acuity  (BCVA).
The  sample  size  calculation  was  performed  considering  a  reduction  in  the  OSDI  score  of  17.6  points  for  the  placebo  group  
at  their  final  visit  versus  a  reduction  of  16.5  points  for  the  treated  group.  Considering  a  ÿ  of  17.1,  a  similar  reduction  in  the  
OSDI  score  is  expected  for  both  treatments,  with  no  statistically  significant  differences  at  their  final  visit.
•  Changes  in  corneal  and  conjunctival  staining  with  lissamine  green.
•  Corneal  and  conjunctival  staining  changes  with  fluorescein.
The  estimated  sample  size  was  101  subjects  (51  subjects  per  arm),  which  was  increased  by  25%  to  account  
for  potential  losses  (25  subjects).  The  estimated  number  of  subjects  (both  eyes)  was  126.
•  Changes  in  tear  film  break-up  time  (TRL)  with  fluorescein.
Security  Variables
The  variables  to  be  considered  in  the  protocol  are  described  below.
Version  3.0
Statistical  Analysis  Plan
SOPH176-1218/I-II
The  calculation  was  performed  using  the  online  tool:  http://powerandsamplesize.com.
Page  5  |  13
6.0  Analysis  Plan
Machine Translated by Google


corrected  (BCVA)  is  a  
test  of  visual  function.
Fraction,  normal  value  =  0.6  to  2.0
Quantitative
Any  event
•  Intensity:
0=Probably  or  possibly  related.
Continue
calm  
without  any  kind  
of  pressure  
and/or  coercion.  See
adverse  
effects  manifested
adverse
1=  Moderate
causal  with  this  
treatment.
(
The  OSDI  is  a
=
Booklet  of
Visual  acuity
corrected  
visual  
acuity  
(BCVA).
Subjects  presenting  AE/Total  number  of  
exposed  subjects.
pharmaceutical  product  and
Spatial  VA  is  the  ability  
to  distinguish  
separate  
elements  of  
an  object  and  identify  
them  as
during  the  
conduct  of  the  
study  will  be
through  the  
electronic  CRF.
Ocular  
Surface  
Disease  Index  
Score
Events
0=  Mild
has  a  relationship
will  apply  
the  questionnaire  
to  the  
subject  and  
allow  him  to  do  so
dry  eye  according  to  
its  symptoms.
Annex  1.  OSDI.
discreet.
2=  Severe
1=Unlikely  related.
The  events
#
Snellen
a  whole.  It  is
•  Nominal  •  Frequency:
adverse  doctor
collected
Score:
that,  not  
necessarily
The  evaluator
)25
Changes  in
that  occurs  in  a  patient  
or  clinical  research  
subject  who  was  
administered  a
questionnaire  
designed  to  
establish  a  severity  
and  
classification  of  the
•  Causality:
(OSDI).
answer  in
Page  6  |  13
Definition
Scale  of
Conceptual
Operational
Table  2.  Operational  Definition  of  the  Variables
Definition
•  Incidence  of  expected  AEs.
Secondary  safety  outcome  variable:
Variable
Category
measurement
Version  3.0
SOPH176-1218/I-II
Statistical  Analysis  Plan
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Changes  of
See  Annex  2.
with
Normal:  >  10  seconds.
Direct  observation  
with  slit  lamp  
and  cobalt  blue  
filter,  Oxford  
scale  
graduation.
Ordinal
See  Annex  2.
Corneal  and  
conjunctival  
staining  changes
corneal  
and  
conjunctival  
staining  with  green
Tear  film  is  usually  
evaluated  
clinically  by  the
epithelial  
defects  in  the  
conjunctiva  and  
cornea.
Qualitative
The  stability  of  the
Detection  of
The  staining  is  presented  in  a  series  of  panels  
(AE).  The  staining  points  range  from  0-5  for  
each  panel  and  from  0-15  for  the  total  
exposed  area  of  conjunctiva  and  cornea.
Degrees:
Qualitative
Oxford  scale.
fluorescein.
Quantitative
tear  film  break-
up  time  (TRPL)  
with  
fluorescein.
Oxford  scale.
Detection  of  
epithelial  
defects  in  the  
conjunctiva  and  
cornea.
end  of  a  blink  and  
you  will  be  asked  
not  to  blink  
immediately  
until  the  tear  
film  on  the  
cornea  
breaks.
Degrees:
It  quantifies  the  minimum  
angle  of  separation  
(located  at  the  
nodal  point  of  the  
eye)  between  two  
objects  that  allows  
them  to  be  
perceived  as  separate  
objects.
Ordinal
Changes  in
direct  with  slit  
lamp,  Oxford  
scale  
graduation.
It  will  be  measured  at
TRL.  This  involves  
instilling  
fluorescein  on  the  ocular  
surface  to  allow  
visualization  of  the  
tear  film  and  measure  
the  time  it  takes  for  the  
tear  film  to  break  up  
after  the  last  blink.
Observation
lissamine.
The  staining  is  presented  in  a  series  of  panels  
(AE).  The  staining  points  range  from  0-5  for  
each  panel  and  from  0-15  for  the  total  
exposed  area  of  conjunctiva  and  cornea.
continues.
Statistical  Analysis  Plan
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Version  3.0
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7.0  Methods  of  Analysis
Page  8  |  13
Version  3.0
SOPH176-1218/I-II
Statistical  Analysis  Plan
Subjects  will  be  divided  into  two  equal  groups,  which  will  be  randomly  and  blindly  assigned  to  one  of  the  PI,  PRO-176  or  
Systane®  Balance  (assignment  (1:1).  Which  will  be  administered  based  on  the  dosage  described  in  the  protocol.
TO.
A  preliminary  safety  analysis  will  be  performed  upon  completion  of  follow-up  of  subject  12  in  the  Nanodrop®  group  (Phase  I).
If  fewer  than  20%  of  unexpected  drug-related  AEs  occur  in  the  Nanodrop®  group,  enrollment  for  the  efficacy  analysis  (Phase  
II)  will  be  completed.  Otherwise,  the  study  will  be  terminated.
Arieh  Daniel  Mercado  Carrizalez
Statistical  analysis  will  be  performed  by  staff  of  Laboratorios  Sophia,  SA  de  CV.  The  statistical  program  SPSS  version  19.0  
(IBM  Corporation,  Armonk,  NY,  USA)  will  be  used.
Initials:  AMC
B.  Juan  De  la  Torre  Orozco
The  designated  personnel  will  be  blinded  to  the  intervention  groups.  Coding  will  be  performed  using  consecutive  numbers  
for  each  intervention  group.
The  results  of  the  continuous  quantitative  variables  will  be  presented  in  measures  of  central  tendency:  mean,  standard  
deviation  and  ranges,  see  table  2.
The  Kolmogorov-Smirnov  and  Shapiro  Wilk  test  will  be  performed  to  determine  whether  the  distribution  is  normal  in  the  
results  obtained  in  each  study  group  (Haffajee  et  al.,  1983).
The  data  will  be  collected  and  organized  in  an  Excel  spreadsheet  (Microsoft®
b.  Initials:  JDO
to.
Office).  The  data  will  then  be  exported  to  the  SPSS  software  platform.  The  variables  will  be  categorized  according  to  their  
nature  (see  Table  2).
Study  participants  will  be  identified  by  a  number  and  their  initials.
The  initials  of  the  subject  of  study  will  be  obtained  starting  with  the  first  letter  of  the  name,  followed  by  the  first  letter  of  the  
first  surname  and  the  first  letter  of  the  second  surname,  obtaining  a  maximum  of  three  letters.  In  case  the  person  has  two  
names  or  a  compound  surname,  the  first  letter  will  always  be  used.
Once  the  subject  has  been  selected,  they  will  be  assigned  a  number  that  will  identify  them  throughout  the  study.  This  code  
will  consist  of  eight  numbers  in  the  following  order  from  left  to  right:
•  Three  digits  of  the  molecule  under  study  according  to  the  sponsor's  designation.  •  Two  digits  corresponding  
to  the  research  center  number.  •  Three  digits  of  the  consecutive  number  assigned  to  its  
inclusion  at  the  research  center.
Example:
Machine Translated by Google


2
Subjects  who  meet  a  minimum  adherence  of  70%  will  be  included  in  the  statistical  analysis  to  meet  
the  study  objective,  based  on  the  weight  of  the  PI.  In  cases  where  the  container  is  not  returned  or  has  
not  been  physically  intact,  adherence  will  be  measured  using  the  subject's  diary.
The  statistical  analysis  of  continuous  quantitative  variables  to  find  significant  differences  (p)  will  be  
as  follows:
•  Intra-group  analysis:  will  be  determined  using  the  Wilcoxon  rank  test,  for  quantitative  variables  
(Woolson,  2008).
•  Difference  between  groups:  Chi-square  test  (X
expected  under  5.
•  Between-group  analysis:  differences  between  groups  will  be  analyzed  using  the  Student  t-test  
or  the  Mann-Whitney  U  statistic  if  applicable  (it  will  be  used  to  test  whether  a  group  of  data  
comes  from  the  same  population).
)  Pearson's  or  Fisher's  exact  test  in  values
The  level  of  difference  to  consider  significance  will  be  an  alpha  (ÿ)  of  0.05  or  less.  It  will  be  considered
•
The  level  of  difference  to  consider  significance  will  be  an  alpha  (ÿ)  of  0.05  or  less.
a  95%  CI  for  non-inferiority  criteria  (Schumi  &  Wittes,  2011;  Easty  et  al.,  2006).
The  result  of  the  nominal  and  ordinal  qualitative  variables  will  be  presented  in  frequencies,  proportions  
and  percentages,  see  table  2.
Statistical  analysis  to  identify  significant  differences  in  qualitative  variables  will  be  performed  by  
creating  2x2  contingency  tables  and  will  be  carried  out  as  follows:
For  the  reporting  of  adverse  events,  all  eyes  of  participants  who  were  randomized  to  an  intervention  
group  after  the  baseline  visit  will  be  considered.
The  final  results  report  will  be  displayed  in  tables  or  graphs,  as  appropriate.
•  Intra-group  difference:  McNemar's  test  (Klingenberg  &  Agresti,  2006).  This  test  is  applied  to  2x2  
contingency  tables  with  a  dichotomous  trait,  with  matched  subject  pairs,  to  determine  whether  
the  marginal  frequencies  of  the  row  and  column  are  equal  (marginal  homogeneity).
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
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DT
EAs
E1
E3
A1
TB
TB  TB
DB
DM
TB
DB
D:  Descriptive  statistics;  T:  2x2  contingency  table;  B:  Bivariate  analysis;  M:  Multivariate  analysis.
Basal
C1
TB  TB  TB
DB  TB  TB
DM
B2
Effectiveness
D1
Ocular  surface  stains
Medical  record
Unexpected/related  AEs
Secondary  outcome
E2
Background
TB
Comprehensive  ophthalmological  evaluation  DT
OSDI
Tear  film  time
TB
Demographics
DT
Security
TB  TB  TB
MAVC
DB  TB  TB
B1
TB
C2
DM
DB  TB  TB
8.0  Changes
Page  10  |  13
A1  B1  B2  C1  C2  D1  E1  E2  E3
The  following  numerals  were  changed  to  match  the  current  version  of  the  protocol:
ÿ  2.0  Study  objectives  (Effectiveness;  phase  II).
ÿ  3.0  Study  design.
Table  3.  Triangulation  of  concepts
Variable  Type  Variable
(Systaine®  Balance).
The  investigational  drug  will  be  considered  safe  and  effective  when  there  are  no  clinical  and  statistical  differences  in  all  
primary  outcome  variables,  with  respect  to  its  comparator.
ÿ  Table  1.  Study  schedule.
ÿ  5.0  Sample  size  calculation.
ÿ  7.0  Methods  of  analysis,  referring  to  adhesion.
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
Machine Translated by Google


12.  Easty  DL,  Nemeth-Wasmer  G,  Vounatsos  JP.,  et  al.  Comparison  of  a  non-preserved  0.1%  T-Gel  eye  gel  
(single  dose  unit)  with  a  preserved  0.1%  T-Gel  eye  gel  (multidose)  in  ocular  hypertension  and  glaucomatous  
patients.  Br  J  Ophthalmol,  2006;  90:574-578.
1.  Benitez-Del-Castillo  JM,  Moreno-Montañés  J,  Jiménez-Alfaro  I,  et  al.  Safety  and  efficacy  clinical  trials  for  
SYL1001,  a  novel  short  interfering  RNA  for  the  treatment  of  dry  eye  disease.
October  1994.
7.  Klingenberg  B.  and  A.  Agresti  A.  Multivariate  extension  of  McNemar's  test.  Biometrics,  2006.  vol.  62,  pp.  
921-928.
Invest  Ophthalmol  Vis  Sci,  2016;  57:6447-6454.
PhD  in  Sciences  Patricia  Muñoz  Villegas.
2.  Chow  et  al.  Sample  Size  Calculations  in  Clinical  Research.  2nd  Ed.  Chapman  &  Hall/CRC
Biostatistics.
Biostatistics  Series,  2008:  Chapter  4,  page  85.
8.  Labetoulle  M,  et  al.  Osmoprotectants,  carboxymethylcellulose  and  hyaluronic  acid  multi-ingredient  eye  drop:  a  randomized  
controlled  trial  in  moderate  to  severe  dry  eye.  Eye,  2017;  31:1409-1416.
9.  Pérez-Balbuena  AL,  et  al.  Efficacy  of  a  fixed  combination  of  0.09%  xanthan  gum/0.1%  chondroitin  sulfate  preservative  free  
vs  polyethylene  glycol/propylene  glycol  in  subjects  with  dry  eye  disease:  a  multicenter  randomized  controlled  trial.  BMC  
Ophthalmol,  2016;  16:164.
Clinical  Operations.
3.  Grubbs  JR,  et  al.  A  review  of  quality  of  life  measures  in  dry  eye  questionnaires.  Cornea,  2014;
10.  Woolson  R.  Wilcoxon  signed-rank  test.  Wiley  Encuclopedia  of  Clinical  Trials,  2008,  pp.  1-3.
33(2):  215-218.
Sophia  Laboratories,  SA  de  CV
11.  Schumi  J  and  Wittes  JT.  Through  the  looking  glass:  understanding  non-inferiority.  trials,
2011;  12:106.
Av.  Paseo  del  Norte  5255,  Guadalajara  Technology  Park.
45010,  Zapopan,  Jalisco,  Mexico.
4.  Haffajee  A.,  Socransky  S.  and  Lindhe  J.  Comparison  of  statistical  methods  of  analysis  of  data  from  clinical  
periodontal  trials.  J  Clin  Periodontol,  1983;  10:  247-256.  5.  http://
powerandsamplesize.com,  equations  based  on;  Chow  et  al.  Sample  Size  Calculations  in  Clinical  Research.  2nd  
Ed.  Chapman  &  Hall/CRC  Biostatistics  Series,  2008.
6.  ICH  E2A.  International  Conference  on  Harmonization  of  Technical  Requirements  for  Registration  of  
Pharmaceuticals  for  Human  Use.  ICH  Harmonized  Tripartitite  Guideline.
Clinical  safety  data  management:  definitions  and  standards  for  expedited  reporting.
Page  11  |  13
9.0  References
Author  of  the  document:
Version  3.0
SOPH176-1218/I-II
Statistical  Analysis  Plan
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0
Driving  at  night.
0
4
during  the  last  week?
Poor  vision.
2
moment.
Almost  at  no  time
4
FREQUENCY
4
moment.
3
1
Almost  in  everything
1
0
3
time
4
3
0
0
3
1
Gritty  feeling  in  the  eyes.
1.  Have  you  experienced  any  of  the  following  changes  during  the  last  week?
In  no  case
0
Subtotal:
3
moment
moment
2
1
Throughout
4
0
2
4
2
2
2.  Have  you  had  eye  problems  that  have  limited  or  prevented  you  from  performing  any  of  the  following  actions?
Blurred  vision.
time
4
50%  of  the
Working  on  a  computer  or  using  
an  ATM.
moment
Wind.
2
time
2
0
moment
moment
FREQUENCY
Throughout
3
In  no  case
3
moment
0
1
Light  sensitivity.
Almost  in  everything
Not  at  any  
time.
1
1
1
Eye  pain
50%  of  the
Subtotal:
FREQUENCY
Almost  in  no
4
4
3
50%  of  the
3
3
Throughout
Read.
Watch  television.
3.  Have  you  experienced  eye  discomfort  in  any  of  the  following  situations  during  the  last  week?
0
moment
Almost  in  everything
1
2
4
1
moment
Almost  in  no
2
2
Page  12  |  13
The  OSDI  (ocular  surface  disease  index)  test  is  a  simple  test  designed  to  establish  the  severity  and  
classification  of  dry  eye  based  on  its  symptoms.
Please  answer  the  following  questions  by  checking  the  box  that  best  represents  your  answer:
10.1  Ocular  Surface  Disease  Index
10.0  Annexes
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
Machine Translated by Google


1
0
Areas  with  air
4
3
2
4
Low  humidity  
(dry)  places.
3
0
Subtotal:
2
1
conditioned.
10.2  Oxford  Scale
)25
=
#
(
Statistical  Analysis  Plan
SOPH176-1218/I-II
Version  3.0
Page  13  |  13
Machine Translated by Google